Tetracyclic pyridone compounds as antivirals

ABSTRACT

The invention provides compounds of Formula (I) 
     
       
         
         
             
             
         
       
     
     as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by hepatitis B virus, and reducing the occurrence of serious conditions associated with HBV.

FIELD OF THE INVENTION

The present invention relates to novel tetracyclic pyridone compoundsthat are inhibitors of hepatitis virus replication, and are thus usefulto treat viral infections, and particularly hepatitis B virus (HBV). Theinvention provides novel tetracyclic pyridone compounds as disclosedherein, pharmaceutical compositions containing such compounds, andmethods of using these compounds and compositions in the treatment andprevention of HBV infections.

BACKGROUND

Globally, over 240 million people are chronically infected withhepatitis B virus (HBV), and more than 2 million reside in the UnitedStates alone. Of those chronically infected patients, up to 40 percentwill eventually develop complications of liver failure from cirrhosis ordevelopment of hepatocellular carcinoma (HCC). Hepatitis B virus (HBV)belongs to the family of Hepadnaviridae, a group of small hepatotropicDNA viruses that replicate through the reverse transcription of an RNAintermediate. The 3.2-kb HBV genome in viral particles is in a circular,partially doublestranded DNA conformation (relaxed circular DNA orrcDNA). The HBV genome consists of four overlapping open reading frames(ORF), which encode for the core, polymerase (Pol), envelope, and Xproteins. rcDNA is transcriptionally inert and must be converted intocovalently closed circular DNA (cccDNA) in the nucleus of infected cellsbefore viral RNAs can be transcribed. cccDNA is the only template forHBV transcription and, because HBV RNA templates genomic reversetranscription, its persistence is required for persistent infection.

The envelope of HBV comprises a mixture of surface antigen proteins(HBsAg). The HBsAg coat is a mixture of three overlapping proteins: allthree share a common region, which corresponds to the smallest of thethree proteins (SHBsAg). The mixture consists mostly of SHBsAg, but alsoincludes Medium HBsAg, which comprises SHBsAg plus an additionalpolypeptide segment, and Large HBsAg, which comprises M HBsAg plusanother added polypeptide segment. In addition to forming the infectiousvirion particle, the S, M and L HBsAg proteins also assemble into asubviral particle knows as the 22-nm particle, which is not infectiousbut contains the same proteins that envelope the infectious virusparticles. Indeed, these subviral, non-infectious particles have beenused as a vaccine, since they contain the same antigenic surfaceproteins that envelope the infectious HBV virion and thus elicitantibodies that recognize the infectious agent. Interestingly, thesesubviral particles greatly outnumber infectious virions, and arebelieved to protect the infectious virions from the immune system of theinfected host. By sheer numbers, they may act as decoys, distractingimmune responses from the infectious virus particles, but in additionthey are reported to suppress the function of immune cells (monocytes,dendritic cells and natural killer cells) and may thus impair the immuneresponse to HBV. Because these subviral particles protect infectious HBVfrom the host immune system, reducing the level of subviral particleshas been recognized as a viable therapeutic approach. See, e.g.,WO2015/113990.

One of the key diagnostic symptoms of chronic HBV is the high serumlevels of the hepatitis B surface antigen (HBsAg). Clinical data inrecent years suggest that sustained virologic response is oftenassociated with on-treatment HBsAg decline during the early phase of thetreatment as early as week 8, while sustained exposure to HBsAg andother viral antigens may lead to HBV-specific immune-tolerance. ChronicHB patients who experienced larger and faster decreases in serum HBsAglevels achieved significantly higher rate (˜40%) of sustained virologicresponse as defined by sustained viral control post treatment.

Current treatment options for HBV include interferon therapies andnucleoside/nucleotide inhibitors of the viral DNA polymerase, such asentecavir and tenofovir. These focus on reduction in the level ofviremia and toleration of hepatic dysfunction, and may have adverseside-effects and also select for drug-resistant virus variants duringlong term therapy. More importantly, these therapies cannot eradicatethe intrahepatic HBV cccDNA pool in chronic hepatitis B patients orlimit the transcription of HBsAg from the pre-existing cccDNA, nor dothey affect the secretion of synthesized HBsAg into patients' blood tocounteract the host innate immune response. As a result, these HBVtreatments are in most cases life-long therapy and discontinuation oftenleads to virological relapse. Some compounds have been reported toreduce serum HBsAg levels but so far have not resulted in new approvedtherapeutic agents. See for example WO2015/113990, WO2015/173164,WO2016/023877, WO2016/071215, and WO2016/128335.

Accordingly, there remains a need for more effective treatments for HBV,especially for treating chronic HBV infections. The invention providescompounds that are believed to operate by suppression of the secretionof the 22 nm subviral particles containing HBsAg. These compounds areuseful to treat HBV infections and to reduce the incidence of seriousliver disorders caused by HBV infections. They also exhibit improvedproperties relative to prior art compounds having similar biologicalactivity, such as improved solubility in buffered aqueous systems andlower predicted propensity for certain adverse effects.

SUMMARY

The present invention provides novel compounds that inhibit secretion ofHBsAg from cells infected with hepatitis B virus and thereby reduceviral load and viral replication in patients having chronic HBVinfection. Some of the compounds of the invention, in addition to beinghighly effective at suppression of HBsAg levels, also exhibit improvedsafety relative to similar compounds known in the art, such as reducedinhibition of sodium ion channels that can be indicative of potentialcardiotoxicity, reduced drug-drug interactions, and lower risk oftime-dependent cytochrome (CYP) inhibition. Thus the compounds of theinvention are suitable for treatment of patients with HBV. The inventionalso provides pharmaceutical compositions containing the novel compoundsas well as methods to use the compounds and compositions to inhibithepatitis B virus replication, and to treat disease conditionsassociated with or caused by HBV. Further objects of this invention aredescribed in the following description and the examples.

In one aspect, the invention provides compounds of Formula (I):

wherein:

R¹ is H, halo, or C₁-C₃ alkyl;

R² is H, halo, CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl, C₁-C₃ alkoxy;

R³ is OH, halo, CN, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₁-C₃ haloalkyl,C₁-C₃ alkoxy, or C₁-C₃ haloalkoxy;

R⁴ is selected from R¹, —OR¹¹, —SR¹¹, and —NRR¹¹;

R¹¹ is C₁-C₄ alkyl, C₃-C₆ cycloalkyl, oxetanyl, tetrahydrofuranyl, ortetrahydropyranyl, each of which is optionally substituted with up tothree groups selected from halo, CN, —OR, C₁-C₃ haloalkoxy, and a 4-7membered heterocyclic group containing one or two heteroatoms selectedfrom N, O and S as ring members that is optionally substituted with oneor two groups selected from halo, oxo, CN, R, —OR, and —NR₂;

R is independently selected at each occurrence from H and C₁-C₃ alkyloptionally substituted with one to three groups selected from halo, —OH,C₁-C₃ alkoxy, oxo, CN, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂, andcyclopropyl;

-   -   and two R groups directly attached to a single atom can        optionally be taken together to form a 3-6 membered ring that        can optionally contain a heteroatom selected from N, O and S as        a ring member, and can be substituted by up to two groups        selected from —OH, oxo, C₁-C₃ alkyl, and C₁-C₃ alkoxy;

R⁵ is H, halo, CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl;

R⁶ is H, halo, C₁-C₃ alkoxy, or C₁-C₆ alkyl;

R⁷ is H, halo, C₁-C₃ alkoxy, or C₁-C₆ alkyl;

R⁸ is H or C₁-C₆ alkyl;

R⁹ taken together with one group selected from R⁶, R⁷ and R⁸ forms a 3-7membered cycloalkyl ring or a 3-7 membered heterocyclic ring containingN, O or S as a ring member; wherein the cycloalkyl or heterocyclic ringis optionally substituted with up to three groups selected from R, —OR,—NR₂, halo, CN, COOR, CONR₂, and oxo;

W is —COOR¹⁰, —C(O)NH—SO₂R, —C(O)NH—SO₂NR₂, 5-tetrazolyl, or1,2,4-oxadiazol-3-yl-5(4H)-one;

R¹⁰ is H or C₁-C₆ alkyl that is optionally substituted with one or twogroups selected from halo, —OR, oxo, CN, —NR₂, COOR, and CONR₂;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

For purposes of interpreting this specification, the followingdefinitions will apply, and whenever appropriate, terms used in thesingular will also include the plural.

Terms used in the specification have the following meanings unless thecontext clearly indicates otherwise:

As used herein, the term “subject” refers to an animal. In certainaspects, the animal is a mammal. A subject also refers to for example,primates (e.g., humans), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a human. A “patient” as used herein refers to a humansubject.

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., slowing or arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In anotherembodiment “treating” or “treatment” refers to alleviating orameliorating at least one physical parameter including those which maynot be discernible by the patient. In yet another embodiment, “treating”or “treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers topreventing or delaying the onset or development or progression of thedisease or disorder.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

“Optionally substituted” means the group referred to can be substitutedat one or more positions by any one or any combination of the radicalslisted thereafter. The number, placement and selection of substituentsis understood to encompass only those substitutions that a skilledchemist would expect to be reasonably stable; thus ‘oxo’ would not be asubstituent on an aryl or heteroaryl ring, for example, and a singlecarbon atom would not have three hydroxy or amino substituents. Unlessotherwise specified, optional substituents are typically up to fourgroups selected from halo, oxo, CN, amino, hydroxy, —C₁₋₃ alkyl, —OR*,—NR*₂, —SR*, —SO₂R*, —COOR*, and —CONR*₂, where each R* is independentlyH or C₁₋₃ alkyl.

“Aryl” as used herein refers to a phenyl or naphthyl group unlessotherwise specified. Aryl groups unless otherwise specified may beoptionally substituted with up to four groups selected from halo, CN,amino, hydroxy, C₁₋₃ alkyl, —OR*, —NR*₂, —SR*, —SO₂R*, —COOR*, and—CONR*₂, where each R* is independently H or C₁₋₃ alkyl.

“Halo” or “halogen”, as used herein, may be fluorine, chlorine, bromineor iodine.

“C₁₋₆ alkyl” or “C₁-C₆ alkyl”, as used herein, denotes straight chain orbranched alkyl having 1-6 carbon atoms. If a different number of carbonatoms is specified, such as C₄ or C₃, then the definition is to beamended accordingly, such as “C₁₋₄ alkyl” will represent methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

“C₁₋₆ alkylene” or “C₁-C₆ alkylene”, as used herein, denotes straightchain or branched alkyl having 1-6 carbon atoms and two open valencesfor connection to two other groups. If a different number of carbonatoms is specified, such as C₄ or C₃, then the definition is to beamended accordingly, such as “C₁₋₄ alkylene” will represent methylene(—CH₂—), ethylene (—CH₂CH₂—), straight chain or branched propylene(—CH₂CH₂CH₂— or —CH₂—CHMe-CH₂—), and the like.

“C₁₋₆ alkoxy”, as used herein, denotes straight chain or branched alkoxy(—O-Alkyl) having 1-6 carbon atoms. If a different number of carbonatoms is specified, such as C₄ or C₃, then the definition is to beamended accordingly, such as “C₁₋₄ alkoxy” will represent methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy andtert-butoxy.

“C₁₋₄ Haloalkyl” or “C₁-C₄ haloalkyl” as used herein, denotes straightchain or branched alkyl having 1-4 carbon atoms wherein at least onehydrogen has been replaced with a halogen. The number of halogenreplacements can be from one up to the number of hydrogen atoms on theunsubstituted alkyl group. If a different number of carbon atoms isspecified, such as C₆ or C₃, then the definition is to be amendedaccordingly. Thus “C₁₋₄ haloalkyl” will represent methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl that have at leastone hydrogen substituted with halogen, such as where the halogen isfluorine: CF₃CF₂—, (CF₃)₂CH—, CH₃—CF₂—, CF₃CF₂—, CF₃, CF₂H—,CF₃CF₂CH(CF₃)— or CF₃CF₂CF₂CF₂—.

“C₃₋₈ cycloalkyl” as used herein refers to a saturated monocyclichydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups includecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If a differentnumber of carbon atoms is specified, such as C₃-C₆, then the definitionis to be amended accordingly.

“4- to 8-Membered heterocyclyl”, “5- to 6-membered heterocyclyl”, “3- to10-membered heterocyclyl”, “3- to 14-membered heterocyclyl”, “4- to14-membered heterocyclyl” and “5- to 14-membered heterocyclyl”, refers,respectively, to 4- to 8-membered, 5- to 6-membered, 3- to 10-membered,3- to 14-membered, 4- to 14-membered and 5- to 14-membered heterocyclicrings; unless otherwise specified, such rings contain 1 to 7, 1 to 5, or1 to 3 heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur as ring members, and the rings may be saturated, orpartially saturated but not aromatic. The heterocyclic group can beattached to another group at a nitrogen or a carbon atom. The term“heterocyclyl” includes single ring groups, fused ring groups andbridged groups. Examples of such heterocyclyl include, but are notlimited to pyrrolidine, piperidine, piperazine, pyrrolidinone,morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran,tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, 8-aza-bicyclo[3.2.1]octane,3,8-diazabicyclo[3.2.1]octane, 3-Oxa-8-aza-bicyclo[3.2.1]octane,8-Oxa-3-aza-bicyclo[3.2.1]octane, 2-Oxa-5-aza-bicyclo[2.2.1]heptane,2,5-Diazabicyclo[2.2.1]heptane, azetidine, ethylenedioxo, oxetane orthiazole. In certain embodiments, if not otherwise specified,heterocyclic groups have 1-2 heteroatoms selected from N, O and S asring members, and 4-7 ring atoms, and are optionally substituted with upto four groups selected from halo, oxo, CN, amino, hydroxy, C₁₋₃ alkyl,—OR*, —NR*₂, —SR*, —SO₂R*, —COOR*, and —CONR*₂, where each R* isindependently H or C₁₋₃ alkyl. In particular, heterocyclic groupscontaining a sulfur atom are optionally substituted with one or two oxogroups on the sulfur.

“Heteroaryl” is a completely unsaturated (aromatic) ring. The term“heteroaryl” refers to a 5-14 membered monocyclic- or bicyclic- ortricyclic-aromatic ring system, having 1 to 8 heteroatoms selected fromN, O or S. Typically, the heteroaryl is a 5-10 membered ring or ringsystem (e.g., 5-7 membered monocyclic group or an 8-10 membered bicyclicgroup), often a 5-6 membered ring containing up to four heteroatomsselected from N, O and S, though often a heteroaryl ring contains nomore than one divalent O or S in the ring. Typical heteroaryl groupsinclude furan, isothiazole, thiadiazole, oxadiazole, indazole, indole,quinoline, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), tetrazolyl, triazine,pyrimidine, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl. Heteroarylgroups are and are optionally substituted with up to four groupsselected from halo, CN, amino, hydroxy, C₁₋₃ alkyl, —OR*, —NR*₂, —SR*,—SO₂R*, —COOR*, and —CONR*₂, where each R* is independently H or C₁₋₃alkyl.

The term “hydroxy” or “hydroxyl” refers to the group —OH.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments. Thefollowing enumerated embodiments are representative of the invention:

1. A compound of formula (I):

wherein:

R¹ is H, halo, or C₁-C₃ alkyl;

R² is H, halo, CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl, C₁-C₃ alkoxy;

R³ is OH, halo, CN, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₁-C₃ haloalkyl,CO₁-3 alkoxy, or C₁-C₃ haloalkoxy;

R⁴ is selected from R¹, —OR¹¹, —SR¹¹, and —NRR¹¹; R¹¹ is C₁-C₄ alkyl,C₃-C₆ cycloalkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl,each of which is optionally substituted with up to three groups selectedfrom halo, CN, —OR, C₁-C₃ haloalkoxy, —NR₂, and a 4-7 memberedheterocyclic group containing one or two heteroatoms selected from N, Oand S as ring members that is optionally substituted with one or twogroups selected from halo, oxo, CN, R, —OR, and —NR₂;

R is independently selected at each occurrence from H and C₁-C₃ alkyloptionally substituted with one to three groups selected from halo, —OH,C₁-C₃ alkoxy, oxo, CN, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂, andcyclopropyl;

-   -   and two R groups directly attached to the same atom, which may        be C or N, can optionally be taken together to form a 3-6        membered ring that can optionally contain an added heteroatom        selected from N, O and S as a ring member, and can be        substituted by up to two groups selected from —OH, oxo, C₁-C₃        alkyl, and C₁-C₃ alkoxy;

R⁵ is H, halo, CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl;

R⁶ is H, halo, C₁-C₃ alkoxy, or C₁-C₆ alkyl;

R⁷ is H, halo, C₁-C₃ alkoxy, or C₁-C₆ alkyl;

R⁸ is H or C₁-C₆ alkyl;

R⁹ taken together with one group selected from R⁶, R⁷ and R⁸ forms a 3-7membered cycloalkyl ring or a 3-7 membered heterocyclic ring containingN, O or S as a ring member; wherein the cycloalkyl or heterocyclic ringis optionally substituted with up to three groups selected from R, —OR,—NR₂, halo, CN, COOR, CONR₂, and oxo;

W is —COOR¹⁰, —C(O)NH—SO₂R, —C(O)NH—SO₂NR₂, 5-tetrazolyl, or1,2,4-oxadiazol-3-yl-5(4H)-one;

R¹⁰ is H or C₁-C₆ alkyl that is optionally substituted with one or twogroups selected from halo, —OR, oxo, CN, —NR₂, COOR, and CONR₂;

or a pharmaceutically acceptable salt thereof.

A preferred option for W in embodiment 1 is —COOH.

2. A compound according to embodiment 1 or a pharmaceutically acceptablesalt thereof, wherein R¹ is H. Alternatively, a compound of embodiment 1wherein R¹ is F or Cl.

3. A compound according to embodiment 1 or embodiment 2 or apharmaceutically acceptable salt thereof, wherein R² is H or halo.

4. A compound according to any one of embodiments 1 to 3 or apharmaceutically acceptable salt thereof, wherein R³ is C₁-C₃ alkoxy orhalo.

5. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein R⁴ is —OR¹¹.

6. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein R⁵ is H or halo.

7. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, which is of the formula:

wherein R⁹ taken together with R⁷ forms a 3-7 membered cycloalkyl ringor a 3-7 membered heterocyclic ring containing N, O or S as a ringmember; wherein the cycloalkyl or heterocyclic ring is optionallysubstituted with up to three groups selected from R, —OR, —NR₂, halo,CN, COOR, CONR₂, and oxo; or a pharmaceutically acceptable salt thereof.

In preferred compounds of this embodiment, the ring formed by R⁹ and R⁷taken together is cis-fused onto the tricyclic core. In certaincompounds of this embodiment, R⁸ is H. Compounds of special interest inthis embodiment include compounds with this absolute stereochemistry:

8. A compound according to any of embodiments 1-6, which is of theformula:

wherein R⁹ taken together with R⁸ forms a 3-7 membered cycloalkyl ringor a 3-7 membered heterocyclic ring containing N, O or S as a ringmember; wherein the cycloalkyl or heterocyclic ring is optionallysubstituted with up to three groups selected from R, —OR, —NR₂, halo,CN, COOR, CONR₂, and oxo; or a pharmaceutically acceptable salt thereof.

9. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein R¹¹ is C₁-C₄ alkyl,optionally substituted with up to two groups selected from halo, CN,—OR, C₁-C₃ haloalkoxy, and a 4-7 membered heterocyclic group containingone or two heteroatoms selected from N, O and S as ring members that isoptionally substituted with one or two groups selected from halo, oxo,CN, R, —OR, and —NR₂.

10. A compound according to any of embodiments 1-9 or a pharmaceuticallyacceptable salt thereof, wherein the R¹¹ is selected from —CH₂CH₂OMe,—CH₂CH₂CH₂OMe, —CH₂—OEt, —CH₂CH₂-Q, and —CH₂CH₂CH₂-Q, where Q isselected from

11. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein

R⁹ taken together with one group selected from R⁶, R⁷ and R⁸ forms a 4-6membered cycloalkyl ring or a 5-6 membered heterocyclic ring containingN, O or S as a ring member; wherein the cycloalkyl or heterocyclic ringis optionally substituted with up to three groups selected from R, —OR,—NR₂, halo, CN, COOR, CONR₂, and oxo.

12. The compound according to embodiment 1, which is selected from:

and the enantiomers of these compounds;or a pharmaceutically acceptable salt thereof. Additional compounds ofembodiment 1 include the following, and their pharmaceuticallyacceptable salts:

13. The compound of any of the Examples, or a pharmaceuticallyacceptable salt thereof. Specific compounds of this embodiment includeany or all of the following:

and the pharmaceutically acceptable salts of these.

14. A pharmaceutical composition, comprising a compound of any of thepreceding embodiments admixed with at least one pharmaceuticallyacceptable carrier.

15. A method to treat a hepatitis B infection, which comprisesadministering to a patient having a hepatitis B infection a compound ofany of embodiments 1-13 or a pharmaceutical composition of embodiment14.

16. The method of embodiment 15, wherein the compound of any one ofclaims 1-13 or the pharmaceutical composition of claim 14 is used incombination with an additional therapeutic agent selected from aninterferon or peginterferon, an HBV polymerase inhibitor, a viral entryinhibitor, a viral maturation inhibitor, a capsid assembly inhibitor, anHBV core modulator, a reverse transcriptase inhibitor, a TLR-agonist, oran immunomodulator.

17. A method to inhibit replication of hepatitis B virus, whichcomprises contacting the hepatitis B virus, either in vitro or in vivo,with a compound according to any one of embodiments 1-13.

18. A compound according to any one of embodiments 1-11, wherein R¹ isF.

Another embodiment of the invention provides a compound as describedabove, or a pharmaceutically acceptable salt thereof, as a medicament.

Also within the scope of this invention is the use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment or prevention of a viraldisease and/or infection in a human being, including HBV.

Included within the scope of this invention are pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier, andoptionally further including an additional pharmaceutically acceptablecarrier or excipient.

According to a further aspect of this embodiment the pharmaceuticalcomposition according to this invention further comprises atherapeutically effective amount of at least one other antiviral agent.

The invention also provides the use of a pharmaceutical composition asdescribed hereinabove for the treatment of a HBV infection in a humanbeing having or at risk of having the infection.

The invention also provides the use of a pharmaceutical composition asdescribed hereinabove for the treatment of HBV infection in a humanbeing having or at risk of having the disease.

Another aspect of the invention involves a method of treating orpreventing a hepatitis B viral disease and/or infection in a human beingby administering to the human being an antivirally effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof,or a composition as described above, alone or in combination with atleast one other antiviral agent, administered together or separately.

An additional aspect of this invention refers to an article ofmanufacture comprising a composition effective to treat a hepatitis Bviral disease and/or infection; and packaging material comprising alabel which indicates that the composition can be used to treat diseaseand/or infection by a hepatitis B virus; wherein the compositioncomprises a compound of formula (I) according to this invention or apharmaceutically acceptable salt thereof.

Still another aspect of this invention relates to a method of inhibitingthe replication of HBV, comprising exposing the virus to an effectiveamount of the compound of formula (I), or a salt thereof, underconditions where replication of the virus is inhibited. This method canbe practiced in vitro or in vivo.

Further included in the scope of the invention is the use of a compoundof formula (I), or a salt thereof, to inhibit the replication of HBV.

In some embodiments, the compound of Formula (I) is co-administered withor used in combination with at least one additional therapeutic agentselected from: an interferon or peginterferon, an HBV polymeraseinhibitor, a viral entry inhibitor, a viral maturation inhibitor, acapsid assembly inhibitor, an HBV core modulator, a reversetranscriptase inhibitor, a TLR-agonist, or an immunomodulator. Someparticular therapeutic agents that may be used in combination with thecompounds of the invention include immunomodulators described herein,interferon alfa 2a, interferon alfa-2b, pegylated interferon alfa-2a,pegylated interferon alfa-2b, TLR-7 and TLR-9 agonists, entecavir,tenofovir, cidofovir, telbivudine, didanosine, zalcitabine, stavudine,lamivudine, abacavir, emtricitabine, apricitabine, atevirapine,ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, adefovir,efavirenz, nevirapine, delavirdine, and etravirine. Suitable coremodulators are disclosed in WO2013/096744; suitable HBV capsidinhibitors are described in US2015/0252057.

These additional agents may be combined with the compounds of thisinvention to create a single pharmaceutical dosage form. Alternativelythese additional agents may be separately administered to the patient aspart of a multiple dosage form, for example, using a kit. Suchadditional agents may be administered to the patient prior to,concurrently with, or following the administration of a compound of theinvention, or a pharmaceutically acceptable salt thereof. Alternatively,these additional therapeutic agents may be administered separately fromand optionally by different routes of administration and on differentdosing schedules from the compound of the invention, provided thecompound of the invention and the additional therapeutic agent are usedconcurrently for treatment of an HBV infection or a disorder caused orcomplicated by an HBV infection.

The dose range of the compounds of the invention applicable per day isusually from 0.01 to 100 mg/kg of body weight, preferably from 0.1 to 50mg/kg of body weight. In some embodiments, the total daily dosage isbetween 1 and 25 mg, and may be administered in a single dose or individed doses at different times to maintain a suitable plasmaconcentration. Each dosage unit may conveniently contain from 5% to 95%active compound (w/w). Preferably such preparations contain from 20% to80% active compound, which is typically admixed with one or morepharmaceutically acceptable carriers or excipients.

The actual pharmaceutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the combination will be administered at dosages andin a manner which allows a pharmaceutically effective amount to bedelivered based upon patient's unique condition.

When the composition of this invention comprises a combination of acompound of the invention and one or more additional therapeutic orprophylactic agent, both the compound and the additional agent may beused at lower dosages than would be used typically for the individualcompound when used as a single-agent treatment. Thus in someembodiments, each component may be present at dosage levels of betweenabout 10 to 100%, and more preferably between about 10 and 80% of thedosage normally administered in a monotherapy regimen.

It is anticipated that the compounds of the invention may be used incombination with other therapeutic agents, just as combinations oftherapeutic agents are currently used for the treatment of hepatitis Cvirus (HCV) infections. Thus a compound of the invention may be used incombination with a different anti-HBV therapeutic agent such as anucleoside or an immunomodulatory agent. These combination therapiesprovide complementary mechanisms to suppress HBV and thus their use incombination should enhance efficacy and also reduce the frequency ofresistance development.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a human being, includingbut not limited to agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina human being. Such agents can be selected from entecavir, tenofovir,cidofovir, telbivudine, didanosine, zalcitabine, stavudine, lamivudine,abacavir, emtricitabine, apricitabine, atevirapine, ribavirin,acyclovir, famciclovir, valacyclovir, ganciclovir, adefovir, efavirenz,nevirapine, delavirdine, and etravirine, and immunomodulators describedherein including interferons and pegylated interferons, TLR-7 agonists,and TLR-9 agonists. Current HBV treatments including immunomodulatoryagents, such as interferon-α and pegylated interferon-α, and oralnucleoside/nucleotide analogues (NAs), including lamivudine, adefovir,telbivudine, entecavir and tenofovir, are known to suppress but noteliminate HBV. J. Antimicrob. Chemother. 2011, vol. 66(12), 2715-25, andthus those therapeutics may be used in combination with a compound ofthe invention.

Many compounds of the invention contain one or more chiral centers.These compounds may be made and used as single isomers or as mixtures ofisomers. Methods for separating the isomers, including diastereomers andenantiomers, are known in the art, and examples of suitable methods aredescribed herein. In certain embodiments, the compounds of the inventionare used as a single substantially pure isomer, meaning at least 90% ofa sample of the compound is the specified isomer and less than 10% ofthe sample is any other isomer or mixture of isomers. Preferably, atleast 95% of the sample is a single isomer. Selection of a suitableisomer is within the ordinary level of skill, as one isomer willtypically be more active in the in vivo or in vitro assay describedherein for measuring HBV activity, and will be the preferred isomer.Where in vitro activity differences between isomers are relativelysmall, e.g. less than about a factor of 4, a preferred isomer may beselected based on activity level against viral replication in cellculture, using methods such as those described herein: the isomer havinga lower MIC (minimum inhibitory concentration) or EC-50 is preferred.

The compounds of the invention may be synthesized by the generalsynthetic routes illustrated below, specific examples of which aredescribed in more detail in the Examples.

The term “an optical isomer” or “a stereoisomer” refers to any of thevarious stereoisomeric configurations which may exist for a givencompound of the present invention and includes geometric isomers. It isunderstood that a substituent may be attached at a chiral center of acarbon atom. The term “chiral” refers to molecules which have theproperty of non-superimposability on their mirror image partner, whilethe term “achiral” refers to molecules which are superimposable on theirmirror image partner. Therefore, the invention includes enantiomers,diastereomers or racemates of the compound. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term isused to designate a racemic mixture where appropriate.“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. Certaincompounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possible isomers oras mixtures thereof, for example as pure optical isomers, or as isomermixtures, such as racemates and diastereoisomer mixtures, depending onthe number of asymmetric carbon atoms. The present invention is meant toinclude all such possible stereoisomers, including racemic mixtures,diasteriomeric mixtures and optically pure forms. Optically active (R)-and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. If the compoundcontains a double bond, the substituent may be E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration. All tautomeric formsare also intended to be included.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers or diastereomers, forexample, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the present invention. “Salts”include in particular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisinvention and, which typically are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, chlorinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Any formula given herein is intended to represent unlabeled forms aswell as isotopically labeled forms of the compounds of the presentinvention having up to three atoms with non-natural isotopedistributions, e.g., sites that are enriched in deuterium or ¹³C or ¹⁵N.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number other than thenatural-abundance mass distribution. Examples of isotopes that can beusefully over-incorporated into compounds of the invention includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴O, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S,³⁶Cl, ¹²⁵I respectively. The invention includes various isotopicallylabeled compounds of the present invention, for example those into whichradioactive isotopes, such as ³H and ¹⁴C, or those in whichnon-radioactive isotopes, such as ²H and ¹³C are present at levelssubstantially above normal isotope distribution. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴C, forexample), reaction kinetic studies (with, for example ²H or ³H),detection or imaging techniques, such as positron emission tomography(PET) or single-photon emission computed tomography (SPECT) includingdrug or substrate tissue distribution assays, or in radioactivetreatment of patients. In particular, an ¹⁸F labeled compound of thepresent invention may be particularly desirable for PET or SPECTstudies. Isotopically-labeled compounds of the present invention cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagenttypically employed. Labeled samples may be useful with quite low isotopeincorporation, such as where a radiolabel is used to detect traceamounts of the compound.

Further, more extensive substitution with heavier isotopes, particularlydeuterium (i.e., ²H or D), may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements or an improvement intherapeutic index. It is understood that deuterium in this context isregarded as a substituent of a compound of the present invention, andtypically a sample of a compound having deuterium as a substituent hasat least 50% deuterium incorporation at the labeled position(s). Theconcentration of such a heavier isotope, specifically deuterium, may bedefined by the isotopic enrichment factor. The term “isotopic enrichmentfactor” as used herein means the ratio between the isotopic abundanceand the natural abundance of a specified isotope. If a substituent in acompound of this invention is denoted deuterium, such compound has anisotopic enrichment factor for each designated deuterium atom of atleast 3500 (52.5% deuterium incorporation at each designated deuteriumatom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%deuterium incorporation), at least 5000 (75% deuterium incorporation),at least 5500 (82.5% deuterium incorporation), at least 6000 (90%deuterium incorporation), at least 6333.3 (95% deuterium incorporation),at least 6466.7 (97% deuterium incorporation), at least 6600 (99%deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d⁶-acetone, d⁶-DMSO.

Compounds of the present invention that contain groups capable of actingas donors and/or acceptors for hydrogen bonds may be capable of formingco-crystals with suitable co-crystal formers. These co-crystals may beprepared from compounds of the present invention by known co-crystalforming procedures. Such procedures include grinding, heating,co-subliming, co-melting, or contacting in solution compounds of thepresent invention with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of the presentinvention.

Methods of Use

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

The compounds of the invention can be administered by known methods,including oral, parenteral, inhalation, and the like. In certainembodiments, the compound of the invention is administered orally, as apill, lozenge, troche, capsule, solution, or suspension. In otherembodiments, a compound of the invention is administered by injection orinfusion. Infusion is typically performed intravenously, often over aperiod of time between about 15 minutes and 4 hours. In otherembodiments, a compound of the invention is administered intranasally orby inhalation; inhalation methods are particularly useful for treatmentof respiratory infections. Compounds of the present invention exhibitoral bioavailability, so oral administration is sometimes preferred.

In certain embodiments of the present invention, a compound of thepresent invention is used in combination with a second antiviral agent,such as those named herein.

By the term “combination”, is meant either a fixed combination in onedosage unit form, as separate dosage forms suitable for use togethereither simultaneously or sequentially, or as a kit of parts for thecombined administration where a compound of the present invention and acombination partner may be administered independently at the same timeor separately within time intervals that especially allow that thecombination partners show a cooperative, e.g., synergistic, effect, orany combination thereof.

The second antiviral agent may be administered in combination with thecompounds of the present inventions wherein the second antiviral agentis administered prior to, simultaneously, or after the compound orcompounds of the present invention. When simultaneous administration ofa compound of the invention with a second agent is desired and the routeof administration is the same, then a compound of the invention may beformulated with a second agent into the same dosage form. An example ofa dosage form containing a compound of the invention and a second agentis a tablet or a capsule.

In some embodiments, a combination of a compound of the invention and asecond antiviral agent may provide synergistic activity. The compound ofthe invention and second antiviral agent may be administered together,separate but simultaneously, or sequentially.

An “effective amount” of a compound is that amount necessary orsufficient to treat or prevent a viral infection and/or a disease orcondition described herein. In an example, an effective amount of acompound of Formula I is an amount sufficient to treat viral infectionin a subject. In another example, an effective amount is an amountsufficient to treat HBV in a subject in need of such treatment. Theeffective amount can vary depending on such factors as the size andweight of the subject, the type of illness, or the particular compoundof the invention. For example, the choice of the compound of theinvention can affect what constitutes an “effective amount.” One ofordinary skill in the art would be able to study the factors containedherein and make the determination regarding the effective amount of thecompounds of the invention without undue experimentation.

The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of a viral infection. Further,several divided dosages, as well as staggered dosages, can beadministered daily or sequentially, or the dose can be continuouslyinfused, or can be a bolus injection. Further, the dosages of thecompound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

Compounds of the invention may be used in the treatment of states,disorders or diseases as described herein, or for the manufacture ofpharmaceutical compositions for use in the treatment of these diseases.The invention provides methods of use of compounds of the presentinvention in the treatment of these diseases or for preparation ofpharmaceutical compositions having compounds of the present inventionfor the treatment of these diseases.

The language “pharmaceutical composition” includes preparations suitablefor administration to mammals, e.g., humans. When the compounds of thepresent invention are administered as pharmaceuticals to mammals, e.g.,humans, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) ofat least one compound of Formula (I) or any subgenus thereof as activeingredient in combination with a pharmaceutically acceptable carrier, oroptionally two or more pharmaceutically acceptable carriers.

The phrase “pharmaceutically acceptable carrier” is art recognized andincludes a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. The carriers include liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject agent from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.Typically, pharmaceutically acceptable carriers are sterilized and/orsubstantially pyrogen-free.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, α-tocopherol, and the like; and metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, inhalation, topical, transdermal, buccal, sublingual, rectal,vaginal and/or parenteral administration. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods well known in the art of pharmacy. The amount of activeingredient that can be combined with a carrier material to produce asingle dosage form will generally be that amount of the compound thatproduces a therapeutic effect. Generally, out of one hundred percent,this amount will range from about 1 percent to about ninety-nine percentof active ingredient, preferably from about 5 percent to about 70percent, most preferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored base, for example, usually sucrose and acacia or tragacanth),powders, granules, or as a solution or a suspension in an aqueous ornon-aqueous liquid, or as an oil-in-water or water-in-oil liquidemulsion, or as an elixir or syrup, or as pastilles (using an inertbase, such as gelatin and glycerin, or sucrose and acacia) and/or asmouth washes and the like, each containing a predetermined amount of acompound of the present invention as an active ingredient. A compound ofthe present invention may also be administered as a bolus, electuary orpaste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluent commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration may comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable carriers suchas sterile isotonic aqueous or nonaqueous solutions, dispersions,suspensions or emulsions, or sterile powders which may be reconstitutedinto sterile injectable solutions or dispersions just prior to use,which may contain antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, glycol ethers, polyols (such as glycerol, propyleneglycol, polyethylene glycol, and the like), and suitable mixturesthereof, vegetable oils, such as olive oil, and injectable organicesters, such as ethyl oleate. Proper fluidity can be maintained, forexample, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc., administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.Intravenous infusion is sometimes a preferred method of delivery forcompounds of the invention. Infusion may be used to deliver a singledaily dose or multiple doses. In some embodiments, a compound of theinvention is administered by infusion over an interval between 15minutes and 4 hours, typically between 0.5 and 3 hours. Such infusionmay be used once per day, twice per day or up to three times per day.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous and subcutaneousdoses of the compounds of this invention for a patient, when used forthe indicated effects, will range from about 0.0001 to about 100 mg perkilogram of body weight per day, more preferably from about 0.01 toabout 50 mg per kg per day, and still more preferably from about 0.1 toabout 20 mg per kg per day. An effective amount is that amount whichprevents or treats a viral infection, such as HBV.

If desired, the effective daily dose of the active compound may beadministered as a single dose per day, or as two, three, four, five, sixor more sub-doses administered separately at appropriate intervalsthroughout the day, optionally, in unit dosage forms. Compoundsdelivered orally or by inhalation, are commonly administered in one tofour doses per day. Compounds delivered by injection are typicallyadministered once per day, or once every other day. Compounds deliveredby infusion are typically administered in one to three doses per day.When multiple doses are administered within a day, the doses may beadministered at intervals of about 4 hours, about 6 hours, about 8 hoursor about 12 hours.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition such as those described herein. Thus methodsof using the compounds of the invention include administering thecompound as a pharmaceutical composition, wherein at least one compoundof the invention is admixed with a pharmaceutically acceptable carrierprior to administration.

Use of Compounds of the Invention in Combination with Immunomodulators

The compounds and compositions described herein can be used oradministered in combination with one or more therapeutic agents that actas immunomodulators, e.g., an activator of a costimulatory molecule, oran inhibitor of an immune-inhibitory molecule, or a vaccine. TheProgrammed Death 1 (PD-1) protein is an inhibitory member of theextended CD28/CTLA4 family of T cell regulators (Okazaki et al. (2002)Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol.170:711-8). PD-1 is expressed on activated B cells, T cells, andmonocytes. PD-1 is an immune-inhibitory protein that negativelyregulates TCR signals (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895;Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother.56(5):739-745), and is up-regulated in chronic infections. Theinteraction between PD-1 and PD-L1 can act as an immune checkpoint,which can lead to, e.g., a decrease in infiltrating lymphocytes, adecrease in T-cell receptor mediated proliferation, and/or immuneevasion by cancerous or infected cells (Dong et al. (2003) J. Mol. Med.81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314;Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immune suppressioncan be reversed by inhibiting the local interaction of PD-1 with PD-L1or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2is blocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).Immunomodulation can be achieved by binding to either theimmune-inhibitory protein (e.g., PD-1) or to binding proteins thatmodulate the inhibitory protein (e.g., PD-L1, PD-L2).

In one embodiment, the combination therapies of the invention include animmunomodulator that is an inhibitor or antagonist of an inhibitorymolecule of an immune checkpoint molecule. In another embodiment theimmunomodulator binds to a protein that naturally inhibits theimmuno-inhibitory checkpoint molecule. When used in combination withantiviral compounds, these immunomodulators can enhance the antiviralresponse, and thus enhance efficacy relative to treatment with theantiviral compound alone.

The term “immune checkpoints” refers to a group of molecules on the cellsurface of CD4 and CD8 T cells. These molecules can effectively serve as“brakes” to down-modulate or inhibit an adaptive immune response. Immunecheckpoint molecules include, but are not limited to, Programmed Death 1(PD-1), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40,CD137, CD40, and LAG3, which directly inhibit immune cells.Immunotherapeutic agents which can act as immune checkpoint inhibitorsuseful in the methods of the present invention, include, but are notlimited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA,TIGIT, LAIR1, CD160, 2B4 and/or TGFR beta. Inhibition of an inhibitorymolecule can be performed by inhibition at the DNA, RNA or proteinlevel. In some embodiments, an inhibitory nucleic acid (e.g., a dsRNA,siRNA or shRNA), can be used to inhibit expression of an inhibitorymolecule. In other embodiments, the inhibitor of an inhibitory signal isa polypeptide, e.g., a soluble ligand, or an antibody or antigen-bindingfragment thereof, that binds to the inhibitory molecule.

By “in combination with,” it is not intended to imply that the therapyor the therapeutic agents must be administered at the same time and/orformulated for delivery together, although these methods of delivery arewithin the scope described herein. The immunomodulator can beadministered concurrently with, prior to, or subsequent to, one or morecompounds of the invention, and optionally one or more additionaltherapies or therapeutic agents. The therapeutic agents in thecombination can be administered in any order. In general, each agentwill be administered at a dose and/or on a time schedule determined forthat agent. It will further be appreciated that the therapeutic agentsutilized in this combination may be administered together in a singlecomposition or administered separately in different compositions. Ingeneral, it is expected that each of the therapeutic agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually.

In certain embodiments, the antiviral compounds described herein areadministered in combination with one or more immunomodulators that areinhibitors of PD-1, PD-L1 and/or PD-L2. Each such inhibitor may be anantibody, an antigen binding fragment thereof, an immunoadhesin, afusion protein, or an oligopeptide. Examples of such immunomodulatorsare known in the art.

In some embodiments, the immunomodulator is an anti-PD-1 antibody chosenfrom MDX-1106, Merck 3475 or CT-011.

In some embodiments, the immunomodulator is an immunoadhesin (e.g., animmunoadhesin comprising an extracellular or PD-1 binding portion ofPD-LI or PD-L2 fused to a constant region (e.g., an Fc region of animmunoglobulin sequence).

In some embodiments, the immunomodulator is a PD-1 inhibitor such asAMP-224.

In some embodiments, the immunomodulator is a PD-LI inhibitor such asanti-PD-LI antibody.

In some embodiments, the immunomodulator is an anti-PD-LI bindingantagonist chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C,or MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-LIantibody described in WO2007/005874. Antibody YW243.55.S70 is ananti-PD-LI described in WO 2010/077634.

In some embodiments, the immunomodulator is nivolumab (CAS RegistryNumber: 946414-94-4). Alternative names for nivolumab include MDX-1106,MDX-1106-04, ONO-4538, or BMS-936558. Nivolumab is a fully human IgG4monoclonal antibody which specifically blocks PD-1. Nivolumab (clone5C4) and other human monoclonal antibodies that specifically bind toPD-1 are disclosed in U.S. Pat. No. 8,008,449, EP2161336 andWO2006/121168.

In some embodiments, the immunomodulator is an anti-PD-1 antibodyPembrolizumab. Pembrolizumab (also referred to as Lambrolizumab,MK-3475, MK03475, SCH-900475 or KEYTRUDA®; Merck) is a humanized IgG4monoclonal antibody that binds to PD-1. Pembrolizumab and otherhumanized anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013)New England Journal of Medicine 369 (2): 134-44, U.S. Pat. No.8,354,509, WO2009/114335, and WO2013/079174.

In some embodiments, the immunomodulator is Pidilizumab (CT-011; CureTech), a humanized IgG1k monoclonal antibody that binds to PD1.Pidilizumab and other humanized anti-PD-1 monoclonal antibodies aredisclosed in WO2009/101611.

Other anti-PD1 antibodies useful as immunomodulators for use in themethods disclosed herein include AMP 514 (Amplimmune), and anti-PD1antibodies disclosed in U.S. Pat. No. 8,609,089, US 2010028330, and/orUS 20120114649. In some embodiments, the anti-PD-L1 antibody isMSB0010718C. MSB0010718C (also referred to as A09-246-2; Merck Serono)is a monoclonal antibody that binds to PD-L1.

In some embodiments, the immunomodulator is MDPL3280A (Genentech/Roche),a human Fc optimized IgG1 monoclonal antibody that binds to PD-L1.MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosedin U.S. Pat. No. 7,943,743 and U.S Publication No.: 20120039906. Otheranti-PD-L1 binding agents useful as immunomodulators for methods of theinvention include YW243.55.S70 (see WO2010/077634), MDX-1105 (alsoreferred to as BMS-936559), and anti-PD-L1 binding agents disclosed inWO2007/005874.

In some embodiments, the immunomodulator is AMP-224 (B7-DCIg;Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342), is aPD-L2 Fc fusion soluble receptor that blocks the interaction between PD1and B7-H1.

In some embodiments, the immunomodulator is an anti-LAG-3 antibody suchas BMS-986016. BMS-986016 (also referred to as BMS986016) is amonoclonal antibody that binds to LAG-3. BMS-986016 and other humanizedanti-LAG-3 antibodies are disclosed in US 2011/0150892, WO2010/019570,and WO2014/008218

In certain embodiments, the combination therapies disclosed hereininclude a modulator of a costimulatory molecule or an inhibitorymolecule, e.g., a co-inhibitory ligand or receptor.

In one embodiment, the costimulatory modulator, e.g., agonist, of acostimulatory molecule is chosen from an agonist (e.g., an agonisticantibody or antigen-binding fragment thereof, or soluble fusion) ofOX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB(CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7,NKp80, CD160, B7-H3 or CD83 ligand.

In another embodiment, the combination therapies disclosed hereininclude an immunomodulator that is a costimulatory molecule, e.g., anagonist associated with a positive signal that includes a costimulatorydomain of CD28, CD27, ICOS and/or GITR.

Exemplary GITR agonists include, e.g., GITR fusion proteins andanti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, aGITR fusion protein described in U.S. Pat. No. 6,111,090, EuropeanPatent No.: 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos.: WO2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g.,in U.S. Pat. No. 7,025,962, European Patent No.: 1947183B1, U.S. Pat.Nos. 7,812,135, 8,388,967, 8,591,886, European Patent No.: EP 1866339,PCT Publication No.: WO 2011/028683, PCT Publication No.: WO2013/039954, PCT Publication No.: WO2005/007190, PCT Publication No.: WO2007/133822, PCT Publication No.: WO2005/055808, PCT Publication No.: WO99/40196, PCT Publication No.: WO 2001/03720, PCT Publication No.:WO99/20758, PCT Publication No.: WO2006/083289, PCT Publication No.: WO2005/115451, U.S. Pat. No. 7,618,632, and PCT Publication No.: WO2011/051726.

In one embodiment, the immunomodulator used is a soluble ligand (e.g., aCTLA-4-Ig), or an antibody or antibody fragment that binds to PD-L1,PD-L2 or CTLA4. For example, the anti-PD-1 antibody molecule can beadministered in combination with an anti-CTLA-4 antibody, e.g.,ipilimumab, for example. Exemplary anti-CTLA4 antibodies includeTremelimumab (IgG2 monoclonal antibody available from Pfizer, formerlyknown as ticilimumab, CP-675,206); and Ipilimumab (CTLA-4 antibody, alsoknown as MDX-010, CAS No. 477202-00-9).

In one embodiment, an anti-PD-1 antibody molecule is administered aftertreatment with a compound of the invention as described herein.

In another embodiment, an anti-PD-1 or PD-L1 antibody molecule isadministered in combination with an anti-LAG-3 antibody or anantigen-binding fragment thereof. In another embodiment, the anti-PD-1or PD-L1 antibody molecule is administered in combination with ananti-TIM-3 antibody or antigen-binding fragment thereof. In yet otherembodiments, the anti-PD-1 or PD-L1 antibody molecule is administered incombination with an anti-LAG-3 antibody and an anti-TIM-3 antibody, orantigen-binding fragments thereof. The combination of antibodies recitedherein can be administered separately, e.g., as separate antibodies, orlinked, e.g., as a bispecific or trispecific antibody molecule. In oneembodiment, a bispecific antibody that includes an anti-PD-1 or PD-L1antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody, orantigen-binding fragment thereof, is administered. In certainembodiments, the combination of antibodies recited herein is used totreat a cancer, e.g., a cancer as described herein (e.g., a solidtumor). The efficacy of the aforesaid combinations can be tested inanimal models known in the art. For example, the animal models to testthe synergistic effect of anti-PD-1 and anti-LAG-3 are described, e.g.,in Woo et al. (2012) Cancer Res. 72(4):917-27).

Exemplary immunomodulators that can be used in the combination therapiesinclude, but are not limited to, e.g., afutuzumab (available fromRoche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®);thalidomide (Thalomid®), actimid (CC4047); and cytokines, e.g., IL-21 orIRX-2 (mixture of human cytokines including interleukin 1, interleukin2, and interferon γ, CAS 951209-71-5, available from IRX Therapeutics).

Exemplary doses of such immunomodulators that can be used in combinationwith the antiviral compounds of the invention include a dose ofanti-PD-1 antibody molecule of about 1 to 10 mg/kg, e.g., 3 mg/kg, and adose of an anti-CTLA-4 antibody, e.g., ipilimumab, of about 3 mg/kg.

Examples of embodiments of the methods of using the antiviral compoundsof the invention in combination with an immunomodulator include these,which may be used along with a compound of Formula I or any subgenus orspecies thereof that is disclosed herein:

i. A method to treat a viral infection in a subject, comprisingadministering to the subject a compound of Formula (I) as describedherein, and an immunomodulator.

ii. The method of embodiment i, wherein the immunomodulator is anactivator of a costimulatory molecule or an inhibitor of an immunecheckpoint molecule.

iii. The method of either of embodiments i and ii, wherein the activatorof the costimulatory molecule is an agonist of one or more of OX40, CD2,CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137),GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160,B7-H3 and CD83 ligand.

iv. The method of any of embodiments i-iii above, wherein the inhibitorof the immune checkpoint molecule is chosen from PD-1, PD-L1, PD-L2,CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

v. The method of any of any of embodiments i-iii, wherein the inhibitorof the immune checkpoint molecule is chosen from an inhibitor of PD-1,PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof.

vi. The method of any of embodiments i-v, wherein the inhibitor of theimmune checkpoint molecule is a soluble ligand or an antibody orantigen-binding fragment thereof, that binds to the immune checkpointmolecule.

vii. The method of any of embodiments i-vi, wherein the antibody orantigen-binding fragment thereof is from an IgG1 or IgG4 (e.g., humanIgG1 or IgG4).

viii. The method of any of embodiments i-vii, wherein the antibody orantigen-binding fragment thereof is altered, e.g., mutated, to increaseor decrease one or more of: Fc receptor binding, antibody glycosylation,the number of cysteine residues, effector cell function, or complementfunction.

ix. The method of any of embodiments i-viii, wherein the antibodymolecule is a bispecific or multispecific antibody molecule that has afirst binding specificity to PD-1 or PD-L1 and a second bindingspecificity to TIM-3, LAG-3, or PD-L2.

x. The method of any of embodiments i-ix, wherein the immunomodulator isan anti-PD-1 antibody chosen from Nivolumab, Pembrolizumab orPidilizumab.

xi. The method of any of embodiments i-x, wherein the immunomodulator isan anti-PD-L1 antibody chosen from YW243.55.S70, MPDL3280A, MEDI-4736,MSB-0010718C, or MDX-1105.

xii. The method of any of embodiments i-x, wherein the immunomodulatoris an anti-LAG-3 antibody molecule.

xiii. The method of embodiment xii, wherein the anti-LAG-3 antibodymolecule is BMS-986016.

xiv. The method of any of embodiments i-x, wherein the immunomodulatoris an anti-PD-1 antibody molecule administered by injection (e.g.,subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g.,about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about3 mg/kg., e.g., once a week to once every 2, 3, or 4 weeks.

xv. The method of embodiment xiv, wherein the anti-PD-1 antibodymolecule is administered at a dose from about 10 to 20 mg/kg every otherweek.

xvi. The method of embodiment xv, wherein the anti-PD-1 antibodymolecule, e.g., nivolumab, is administered intravenously at a dose fromabout 1 mg/kg to 3 mg/kg, e.g., about 1 mg/kg, 2 mg/kg or 3 mg/kg, everytwo weeks.

xvii. The method of embodiment xv, wherein the anti-PD-1 antibodymolecule, e.g., nivolumab, is administered intravenously at a dose ofabout 2 mg/kg at 3-week intervals.

The compounds of the invention share certain structural features withcompounds reported to have the same utility as the compounds of theinvention. For example, Example 132 in WO2015/113990 has this structure:

and similar biological activity to the compounds of the invention. Asillustrated herein, certain compounds of the invention have improvedsolubility and safety profiles when compared to the reference example incommon screens that are used to predict suitability for development.

The compounds as described herein may be synthesized by the generalsynthetic routes below, specific examples of which are described in moredetail in the Examples.

General Synthetic Procedures

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesize thecompounds of the invention are either commercially available or can beproduced by organic synthesis methods known to one of ordinary skill inthe art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme,Volume 21). General methods for synthesis of compounds of the inventionare illustrated by the Examples below, and by methods disclosed inpublished PCT applications WO2015/113990 and WO2015/173164.

LIST OF ABBREVIATIONS

-   -   Ac acetyl    -   ACN Acetonitrile    -   AcOEt/EtOAc Ethyl acetate    -   AcOH acetic acid    -   aq aqueous    -   Bn benzyl    -   Bu butyl (nBu=n-butyl, tBu=tert-butyl)    -   CDI Carbonyldiimidazole    -   DBU 1,8-Diazabicyclo[5.4.0]-undec-7-ene    -   Boc2O di-tert-butyl dicarbonate    -   DCE 1,2-Dichloroethane    -   DCM Dichloromethane    -   DIAD Diisopropyl azodicarboxylate    -   DiBAI-H Diisobutylaluminum Hydride    -   DIPEA N-Ethyldiisopropylamine    -   DMA N, N-dimethylacetamide    -   DMAP Dimethylaminopyridine    -   DMF N,N′-Dimethylformamide    -   DMSO Dimethylsulfoxide    -   EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   EI Electrospray ionisation    -   Et₂O Diethylether    -   Et₃N Triethylamine    -   Ether Diethylether    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   FA Formic acid    -   FC Flash Chromatography    -   h hour(s)    -   HCl Hydrochloric acid    -   HOBt 1-Hydroxybenzotriazole    -   HPLC High Performance Liquid Chromatography    -   H₂O Water    -   IPA isopropanol    -   L liter(s)    -   LC-MS Liquid Chromatography Mass Spectrometry    -   LiHMDS Lithium bis(trimethylsilyl)amide    -   Me methyl    -   MeI Iodomethane    -   MeOH Methanol    -   mg milligram    -   min minute(s)    -   mL milliliter    -   MS Mass Spectrometry    -   Pd/C palladium on charcoal    -   PG protecting group    -   Ph phenyl    -   Ph₃P triphenyl phosphine    -   Prep Preparative    -   Rf ratio of fronts    -   RP reverse phase    -   Rt Retention time    -   rt Room temperature    -   SFC Supercritical Fluid Chromatography    -   SiO₂ Silica gel    -   T3P® Propylphosphonic acid anhydride    -   TBAF Tetrabutylammonium fluoride    -   TBDMS t-Butyldimethylsilyl    -   TEA Triethylamine    -   TFA Trifluoroacetic acid    -   THF Tetrahydrofuran    -   TLC Thin Layer Chromatography    -   TsCl toluene sulfonyl chloride

Within the scope of this text, a readily removable group that is not aconstituent of the particular desired end product of the compounds ofthe present invention is designated a “protecting group,” unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such ase.g., Science of Synthesis: Houben-Weyl Methods of MolecularTransformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp.(URL: http://www.science-of-synthesis.com (Electronic Version, 48Volumes)); J. F. W. McOmie, “Protective Groups in Organic Chemistry”,Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley,New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.Meienhofer), Academic Press, London and New York 1981, in “Methoden derorganischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4thedition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jeschkeit, “Aminosauren, Peptide, Proteine” (Amino acids,Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideund Derivate” (Chemistry of Carbohydrates: Monosaccharides andDerivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic ofprotecting groups is that they can be removed readily (i.e., without theoccurrence of undesired secondary reactions) for example by solvolysis,reduction, photolysis or alternatively under physiological conditions(e.g., by enzymatic cleavage).

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g., the sodium salt of 2-ethyl hexanoic acid, with organicalkali metal or alkaline earth metal compounds, such as thecorresponding hydroxides, carbonates or hydrogen carbonates, such assodium or potassium hydroxide, carbonate or hydrogen carbonate, withcorresponding calcium compounds or with ammonia or a suitable organicamine, stoichiometric amounts or only a small excess of the salt-formingagent preferably being used. Acid addition salts of compounds of thepresent invention are obtained in customary manner, e.g., by treatingthe compounds with an acid or a suitable anion exchange reagent.Internal salts of compounds of the present invention containing acid andbasic salt-forming groups, e.g., a free carboxy group and a free aminogroup, may be formed, e.g., by the neutralization of salts, such as acidaddition salts, to the isoelectric point, e.g., with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallization and/or chromatographicseparation, for example over silica gel or by, e.g., medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallization, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g., using chromatographic methods,distribution methods, (re-) crystallization, and the like.

EXAMPLES

The invention is illustrated by the following examples, which should notbe construed as limiting. The assays used throughout the Examples arewell established in the art: demonstration of efficacy in these assaysis generally regarded as predictive of efficacy in subjects.

General Conditions:

Mass spectra were run on LC-MS systems using electrospray ionization.These were WATERS Acquity Single Quard Detector. [M+H]⁺ refers tomono-isotopic molecular weights. NMR spectra were run on open accessVarian 400 or Varian 500 NMR spectrometers. Spectra were measured at298K and were referenced using the solvent peak. Chemical shifts for ¹HNMR are reported in parts per million (ppm). Mass spectra were run onLC-MS systems with one of the following conditions:

1. Waters Acquity UPLC-H class system equipped with SQD detector.

Column: ACQUITY UPLC HSS C18 (50*2.1) mm, 1.8 u.

Column temperature: Ambient.

Mobile Phase: A) 0.1% FA+5 mM Ammonium Acetate in Water.

-   -   B) 0.1% FA in Acetonitrile.        Gradient: 5-5% solvent B in 0.40 min, 5-35% solvent B in 0.80        min, 35-55% solvent B in 1.2 min,    -   55-100% solvent B in 2.5 min.        Flow rate: 0.55 mL/min.        Compounds were detected by a Waters Photodiode Array Detector.

2. Waters LCMS system equipped with ZQ 2000 detector.

Column: X-BRIDGE C18 (50*4.6) mm, 3.5 u.

Column temperature: Ambient.

Mobile Phase: A) 0.1% NH₃ in Water.

-   -   B) 0.1% NH₃ in Acetonitrile.        Gradient: 5-95% solvent B in 5.00 min.        Flow rate: 1.0 mL/min.        Compounds were detected by a Waters Photodiode Array Detector.

3. Waters ACQUITY UPLC system and equipped with a ZQ 2000 MS system.

Column: Kinetex by Phenomenex, 2.6 um, 2.1×50 mm

Column temperature: 50° C.Gradient: 2-88% (or 00-45%, or 65-95%) solvent B over a 1.29 min periodFlow rate: 1.2 mL/min.Compounds were detected by a Waters Photodiode Array Detector.

Example 1: Synthesis of Racemic10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [rac-1]

Step 1:5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanone[1.1a]

A mixture of Pd(OAc)₂ (8.16 mg, 0.036 mmol), sodium tert-butoxide (0.454g, 4.72 mmol), dicyclohexyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphane (32mg), 2,2-dimethylcyclopentanone (0.547 ml, 4.36 mmol) and4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (1 g, 3.63 mmol) intoluene (4.0 mL) was heated in a sealed vial at 50° C. for 18 hours. Themixture was diluted with EtOAc and filtered. The filtrate wasconcentrated and the remaining oil was purified by silica gel columnchromatography, EtOAc/heptane 5 to 50%, to give product (500 mg, 45%yield). LC-MS (m/z): 307.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.72-7.28(m, 1H), 6.94-6.61 (m, 2H), 4.10 (m, 2H), 3.91-3.77 (m, 4H), 3.65-3.49(m, 2H), 3.41-3.27 (m, 3H), 2.36 (d, J=4.2 Hz, 1H), 2.19-1.88 (m, 4H),1.88-1.71 (m, 1H), 1.21-1.11 (m, 3H), 1.07 (s, 3H)

Step 2:5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanamine[1.1b]

To the mixture of5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanone (320mg, 1.0 mmol) in MeOH (3 mL) was added acetic acid ammonia salt (1.6 g,20.9 mmol) and sodium cyanoborohydride (656 mg, 10.4 mmol). The mixturewas stirred at 80° C. for 8 hours and then was concentrated underreduced pressure. The remaining material was diluted with EtOAc, washedwith water and brine, dried over Na₂SO₄ and concentrated. The crudematerial was used in the next step with no further purification. LCMS(m/z): 308.0 [M+H]⁺.

Step 3: N-(5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2dimethylcyclopentyl)formamide [1.1c]

To the mixture of5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanamine(320 mg, 1.041 mmol) in dioxane (3 ml) was added formic acid (0.160 mL,4.16 mmol). The mixture was stirred at 100° C. for 6 hours. The mixturewas concentrated to afford the crude product which was used in the nextstep with no further purification. LCMS (m/z): 336.2 [M+H]⁺.

Step 4:7-methoxy-8-(3-methoxypropoxy)-3,3-dimethyl-2,3,3a,9b-tetrahydro-1H-cyclopenta[c]isoquinoline[1.1d-I] and [1.1d-II]

To a mixture ofN-(5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentyl)formamide(349 mg, 1.04 mmol) in acetonitrile (1.8 ml) was added POCl₃ (140 μl,1.50 mmol). The mixture was stirred at 85° C. for 2 hours and thenconcentrated. The residue was dissolved in EtOAc and basified by addingammonium hydroxide solution. The phases were separated and the organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theremaining material was purified by silica gel chromatography,acetone/heptane 5 to 50% to give product rac-1.1d-I and rac-1.1d-II.

Trans isomer rac-1.1d-II: (70 mg, 21% yield). LCMS (m/z): 318.3 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.22 (s, 1H), 6.93-6.83 (m, 1H), 6.70 (s, 1H),4.16 (t, J=6.4 Hz, 2H), 3.94-3.83 (m, 3H), 3.57 (q, J=4.7 Hz, 2H), 3.35(d, J=1.5 Hz, 4H), 2.84 (s, 2H), 2.21-1.98 (m, 4H), 1.84-1.70 (m, 3H),1.68-1.53 (m, 3H), 1.22 (s, 4H), 1.06 (s, 4H)

Cis isomer rac-1.1d-I: (54 mg, 16% yield). LCMS (m/z): 318.3 [M+H]⁺. 1HNMR (400 MHz, CDCl₃): 8.17 (s, 1H), 6.75 (s, 1H), 6.67 (s, 1H), 4.14 (t,J=6.2 Hz, 3H), 3.92-3.83 (m, 3H), 3.77 (d, J=10.3 Hz, 1H), 3.57 (t,J=5.4 Hz, 3H), 3.35 (d, J=1.6 Hz, 3H), 3.25 (q, J=9.4 Hz, 1H), 2.42-2.21(m, 2H), 2.19-2.01 (m, 3H), 1.64 (dd, J=20.6, 7.8 Hz, 4H), 1.45 (t,J=8.0 Hz, 2H), 1.24 (d, J=6.1 Hz, 4H), 0.89 (s, 4H).

The relative configuration of rac-1.1d-I and rac-1.1d-II were confirmedby nuclear Overhauser effect (nOe) experiments.

Step 5: Ethyl10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,8,8a,12b-octahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylate[rac-1.1e]

To a mixture of7-methoxy-8-(3-methoxypropoxy)-3,3-dimethyl-2,3,3a,9b-tetrahydro-1H-cyclopenta[c]isoquinoline(cis isomer, rac-1.1d-I) (51 mg, 0.161 mmol) in EtOH (0.6 ml) was added(Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate (90 mg, 0.482 mmol). Themixture was stirred at 110° C. for 16 hours. After cooling, the mixturewas concentrated and the crude material was used in the next step withno further purification. LCMS (m/z): 458.0 [M+H]⁺.

Step 6: Ethyl10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylate[rac-1.1f]

To a mixture of ethyl10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,8,8a,12b-octahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylate (73.7mg, 0.161 mmol) in DME (0.3 ml) was added p-chloranil (39.6 mg, 0.161mmol). The mixture was stirred at 110° C. for 2 hours. After cooling tort, the mixture was filtered and the solid was washed with cold DME.After drying, the desired product (28 mg, 38% yield) was a light yellowsolid. LCMS (m/z): 456.0 [M+H]⁺.

Step 7: racemic10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [rac-1]

To a mixture of ethyl10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylate(28 mg, 0.061 mmol) in THF (0.4 ml), MeOH (0.4 ml) and water (0.4 ml)was added LiOH (4.42 mg, 0.184 mmol). After stirring at rt for 2 hours,the mixture was concentrated and then acidified by adding 3.0 N HCl aqsolution. To the mixture was added EtOAc. The organic layer was washedwith water and brine, dried, and concentrated. The crude residue waspurified by reverse phase HPLC to give product (5 mg, 19% yield). LCMS(m/z): 428.2 [M+H]⁺. 1H NMR (400 MHz, CD₃CN): 8.41 (s, 1H), 7.33 (d,J=22.5 Hz, 2H), 6.97 (s, 1H), 4.38 (d, J=8.5 Hz, 1H), 4.17 (dtd, J=13.1,9.6, 4.8 Hz, 2H), 3.91 (s, 3H), 3.80 (t, J=8.9 Hz, 1H), 3.53 (t, J=6.2Hz, 3H), 3.32 (s, 3H), 2.32 (q, J=7.7 Hz, 4H), 2.13-2.00 (m, 3H), 1.65(dt, J=13.2, 6.8 Hz, 2H), 1.45 (dt, J=12.9, 7.9 Hz, 1H), 1.22 (s, 3H),0.48 (s, 3H).

Chiral Separation:(3aS,12bR)-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [1.1] and(3aR,12bS)-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [1.2]

Compound rac-1 (40 mg, 0.090 mmol) was separated by chiral HPLC (Column:AD 21×250 mm, Heptane/IPA=30/70, flow rate 20 ml/min) to afford the twoenantiomers 1.1 and 1.2.

Compound 1.1: tR 9.55 min; 8 mg 20% yield. LCMS (m/z): 428.2 [M+H]⁺. 1 HNMR (400 MHz, CD₃CN): 8.41 (s, 1H), 7.33 (d, J=22.5 Hz, 2H), 6.97 (s,1H), 4.38 (d, J=8.5 Hz, 1H), 4.17 (dtd, J=13.1, 9.6, 4.8 Hz, 2H), 3.91(s, 3H), 3.80 (t, J=8.9 Hz, 1H), 3.53 (t, J=6.2 Hz, 3H), 3.32 (s, 3H),2.32 (q, J=7.7 Hz, 4H), 2.13-2.00 (m, 3H), 1.65 (dt, J=13.2, 6.8 Hz,2H), 1.45 (dt, J=12.9, 7.9 Hz, 1H), 1.22 (s, 3H), 0.48 (s, 3H).

Compound 1:2: tR 18.90 min, 8 mg, 20% yield. LCMS (m/z): 428.2 [M+H]⁺. 1H NMR (400 MHz, CD₃CN): 8.41 (s, 1H), 7.33 (d, J=22.5 Hz, 2H), 6.97 (s,1H), 4.38 (d, J=8.5 Hz, 1H), 4.17 (dtd, J=13.1, 9.6, 4.8 Hz, 2H), 3.91(s, 3H), 3.80 (t, J=8.9 Hz, 1H), 3.53 (t, J=6.2 Hz, 3H), 3.32 (s, 3H),2.32 (q, J=7.7 Hz, 4H), 2.13-2.00 (m, 3H), 1.65 (dt, J=13.2, 6.8 Hz,2H), 1.45 (dt, J=12.9, 7.9 Hz, 1H), 1.22 (s, 3H), 0.48 (s, 3H).

Example 2: Synthesis of Racemic10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [rac-2]

Using the trans-fused isomer from Step 4 of Example 1, the titlecompound was prepared by the same method used to make Example 1. LCMS(m/z): 428.2 [M+H]⁺. 1 H NMR (400 MHz, CD₃CN): δ 8.72 (s, 1H), 7.34 (s,1H), 7.23 (s, 1H), 6.84 (s, 1H), 4.17 (q, J=6.4 Hz, 2H), 3.90 (s, 3H),3.74 (d, J=13.5 Hz, 1H), 3.60-3.42 (m, 4H), 3.32 (s, 4H), 2.31 (dq,J=17.6, 7.9, 6.3 Hz, 2H), 2.10-2.00 (m, 3H), 1.52 (s, 4H), 1.29 (s, 4H)

Example 3.1: Synthesis of(3aS,12bR)-8-fluoro-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid Step 1: ethyl(Z)-2-(ethoxymethylene)-4,4-difluoro-3-((trimethylsilyl)oxy)but-3-enoate[3.1a]

Under an argon atmosphere, a mixture of Mg (3.69 g, 152 mmol)) and TMSCl(19.43 mL, 152 mmol) was treated with ultrasound irradiation for 15 min.To the mixture was added DMF (30 mL)), ethyl(Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (4.56 g, 19 mmol)was added dropwise at 50° C. under an argon atmosphere. The reactionmixture was stirred for additional 3 min. at 50° C. After removal ofexcess TMSCl in vacuo, the crude mixture was filtered and the filtrate(containing 3.1a and DMF) was used in the next step without furtherpurification.

Step 2: ethyl8-fluoro-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylate[3.1b-1] and [3.1b-2]

To a suspension of ZnI₂ (920 mg, 2.88 mmol)) and 1.1d-I (915 mg, 2.88mmol) in dry MeCN (10 mL), a solution of crude 3.1a (5091 mg, 17.30mmol) in dry DMF (30 mL) was added dropwise at 50° C., and the reactionmixture was stirred overnight. The reaction mixture was poured into 10%HCl and extracted with DCM. The organic layer was washed with brine, anddried over MgSO₄. After filtration, the organic layer was concentratedand the crude oil purified by silica gel chromatography (0-10%MeOH/EtOAc) to afford rac-3.1 b (1.2 g, 2.53 mmol, 88% yield)) as a paleyellow solid. The material was then purified by chiral SFC (AD column,flow rate 100 ml/min, CO₂/EtOH=70/30, 256 bar) to provide to provideproducts 3.1b-1 (tR 2.4 min) and 3.1b-2 (tR 4.4 min, 280 mg). LC-MS(m/z): 474.2 [M+H]⁺.

Step 3:(3aS,12bR)-8-fluoro-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [3.1]

To the solution of 3.1b-2 (330 mg, 0.697 mmol) in THF (1 mL) was addedNaOH (1.394 mL, 1.394 mmol). The reaction mixture was stirred for 2 h,then the reaction was acidified with 1.5 ml 1N HCl and extracted withdichloromethane. The organic layer was washed with brine, and dried overMgSO₄. After filtration and concentration, the resultant solid wasrecrystallized from hot EtOH/Water (5 ml; 5 ml) and the solids collectedby vacuum filtration. The material was further lyophilized from MeCN andwater to give product (230 mg, 0.511 mmol, 73.3%) as a tan solid. LC-MS(m/z): 446.4 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d³) δ 8.82 (s, 1H), 7.56 (s,1H), 7.20 (s, 1H), 4.52 (d, J=5.5 Hz, 1H), 4.20-4.06 (m, 2H), 3.82 (s,3H), 3.31 (dd, J=15.9, 4.8 Hz, 2H), 3.26 (s, 3H), 3.18 (d, J=15.9 Hz,1H), 2.01 (p, J=6.3 Hz, 2H), 1.57-1.50 (m, 1H), 0.87 (d, J=6.6 Hz, 3H),0.73 (d, J=6.7 Hz, 3H).

Compound 3.2 was synthesized from 3.1b-1 following step 3 procedure.LC-MS (m/z): 446.2 [M+H]⁺.

Example 4.1: Synthesis of(3aR,12bR)-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-2H-furo[3,2-c]pyrido[2,1-a]isoquinoline-6-carboxylicacid

Step 1:4-(benzyloxy)-1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3,3-dimethylbutan-2-one

A 250 mL oven-dried round-bottomed flask was charged with4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (6.7 g, 24.35 mmol), XPhos(0.348 g, 0.731 mmol), Pd(OAc)₂ (0.082 g, 0.365 mmol) and purged withnitrogen. Dioxane (Volume: 32.5 ml) was added and the mixture stirreduntil homogeneous. LiHMDS (1.0 M in THF, 70.6 ml, 70.6 mmol) was added.4-(Benzyloxy)-3,3-dimethylbutan-2-one (10.05 g, 48.7 mmol) in 4 mLdioxane was added slowly. The flask was fitted with a nitrogen-purgedreflux condenser and then heated to 71° C. for 90 min. After cooling,the mixture was poured into water and the pH brought to 3 with 4 N HCl.The aqueous layer was extracted thrice with EtOAc, the combined organiclayers were dried over Na₂SO₄, and then concentrated onto 16 gdiatomaceous earth. The material was purified on a 120 g SiO2 Combiflashcartridge (0->50% EtOAc in heptanes). The major UV active peak wasconcentrated to provide 4.1a (8.8 g, 21.97 mmol, 90% yield) as a yellowoil. LC-MS (m/z): 401.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.28-7.36 (m,5H), 6.79 (d, J=8.2 Hz, 1H) 6.6-6.7 (m, 2H), 4.51 (s, 2H), 4.04 (t,J=6.5 Hz), 2H), 3.83 (s, 3H), 3.75 (s, 2H), 3.55 (t, J=6.2 Hz, 2H), 3.51(s, 2H), 3.34 (s, 3H), 2.07 (quint, J=6.3 Hz, 2H), 1.20 (s, 6H).

Step 2:4-(benzyloxy)-1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3,3-dimethylbutan-2-amine[4.1b]

A round-bottomed flask was charged with 4.1a (600. mg, 1.498 mmol) andmethanol (1.5 mL). Ammonium acetate (1.732 g, 22.47 mmol) was added andthe mixture was stirred at rt for 30 mins then sodium cyanoborohydride(471 mg, 7.49 mmol) was added. The mixture was heated at 60° C. untilthe reaction for 18 h. The reaction was quenched by adding 6 N NaOH andstirring for 30 min. The mixture was extracted twice with 2-Me-THF, thecombined organic layers dried over Na₂SO₄, and then filtered andconcentrated to provide crude 4.1 b (602 mg, 1.498 mmol, 100% yield)that was used without further purification. LC-MS (m/z): 402.4 [M+H]⁺.

Step 3:N-(4-(benzyloxy)-1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3,3-dimethylbutan-2-yl)formamide[4.1c]

4.1 b (600 mg, 1.494 mmol) was taken up in DMF (2.3 ml) and cooled to 0°C. Triethylamine (1.04 mL, 7.5 mmol), was added followed by EDC (573 mg,2.99 mmol) and formic acid (229 μl, 5.98 mmol). The mixture was stirredat rt for 2 hours. Water was added and the mixture was extracted withEtOAc. The combined organic layers were washed with 1.0 H aq HClsolution, brine, then dried over Na₂SO₄ and concentrated. The crudematerial was purified by silica gel (0->70% acetone in heptane) to give4.1c (520 mg, 1.211 mmol, 81% yield) as a yellow oil. LC-MS (m/z): 430.3[M+H]⁺.

Step 4:3-(1-(benzyloxy)-2-methylpropan-2-yl)-7-methoxy-6-(3-methoxypropoxy)-3,4-dihydroisoquinoline[4.1d]

A 200 mL round-bottomed flask was charged with 4.1c (4.71 g, 10.96 mmol)and purged with nitrogen. Acetonitrile (Volume: 43.8 ml) was added, andthe flask cooled to 0-5° C. POCl₃ (1.532 ml, 16.44 mmol) was addeddropwise. The flask was fitted with a dry condenser and the mixture washeated to 70° C. for 1 hr. The mixture was cooled to rt and thevolatiles were removed on the rotary evaporator. The resultant oil wasdiluted with EtOAc and water, then basified with sat. NH₄OH until theaqueous layer reached pH 11. The layers were separated and the aqueouslayer was extracted with EtOAc twice. The organic phases were combined,dried over Na₂SO₄, filtered and concentrated onto 6 g diatomaceous earthand purified on a 40 g SiO2 Combiflash column (0->60% acetone/heptane)to provide 4.1d (3.8 g, 84% yield) as an oil. LC-MS (m/z): 412.5 [M+H]⁺.

Step 5: ethyl6-(1-(benzyloxy)-2-methylpropan-2-yl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate[4.1e]

To a solution of 4.1d (3.5 g, 8.50 mmol) in EtOH (Volume: 8.50 ml,Ratio: 1.000) was added (Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate(5.92 ml, 34.0 mmol) in a 20 mL microwave vial. The mixture was thensealed and flushed with nitrogen. The vial was heated at 110° C. for 18hours. The reaction mixture was concentrated to dryness under vacuum. Tothe residue was added DME (Volume: 8.50 ml, Ratio: 1.000) andP-CHLORANIL (2.509 g, 10.21 mmol). The vial was sealed and heated at100° C. for 1 hour. The solvent was removed and the residue loaded onto12 g diatomaceous earth and purified by silica gel column chromatography(IPA/EtOAc 0->70%) to provide 4.1e (3.5 g, 75%) as a clear oil. LC-MS(m/z): 550.5 [M+H]⁺.

Step 6: ethyl6-(1-hydroxy-2-methylpropan-2-yl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate[4.1f]

A mixture of 4.1e (600 mg, 1.092 mmol) and 10% Pd/C (349 mg, 0.327 mmol)in EtOH (Volume: 10 mL) was purged with H₂ and stirred for 4 h. Afterfiltration, the filtrate was concentrated to dryness to give the crudematerial which was purified by silica gel chromatography (0-50%MeOH/EtOAc) to give 4.1f (353 mg, 0.768 mmol, 70.4% yield) as an oil.LC-MS (m/z): 460.3 [M+H]⁺.

Step 7: ethyl(3aR*,12bR*)-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-2H-furo[3,2-c]pyrido[2,1-a]isoquinoline-6-carboxylate[4.1g]

To a solution of 4.1f (311 mg, 0.677 mmol) in acetonitrile (9 mL) wasadded a solution of CuSO₄ (108 mg, 0.677 mmol) and K₂S₂O₈ (366 mg, 1.354mmol) in water (Volume: 1.9 mL). The resulting mixture was stirred atreflux for 1 hour. The mixture was added 100 mL ethyl acetate, washedwith water, brine and dried over Na₂SO₄. The organic phase wasconcentrated and the residue was used in the next step without furtherpurification. The crude residue was treated with a mixture of 2 mLAcOH/0.1 mL H₂SO₄. After stirred for 20 mins at room temperature, themixture was added 100 ml DCM, washed with saturated NaHCO₃, dried overNa₂SO₄. The organic phase was concentrated and the residue was purifiedby silica get chromatography (0-70% IPA/EA) to give product 4.1g (180mg, 60.4%).

Step 8:(3aR,12bR)-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-2H-furo[3,2-c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [4.1]

LiOH (3.28 ml, 6.56 mmol) in water was added to a solution of 4.1g (1.2g, 2.62 mmol) in THF (8.74 ml) and the mixture was stirred for 30 min.The solution was then acidified by adding 4.0 N HCl, diluted with water,and extracted thrice with DCM. The combined organic layers were driedover Na₂SO₄, filtered and concentrated. The material was purified bychiral chromatography (AD column, SFC 5 mL/min, CO₂/IPA=70/30), andreturned as 4.1 (1.36 min) and 4.2 (1.86 min). 4.1 (348 mg, 0.802 mmol,30.6% yield) was a fluffy solid after lyophilization from MeCN/H₂O.LC-MS (m/z): 430.4 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d6): 8.60 (s, 1H), 7.66(s, 1H), 7.56 (s, 1H), 7.06 (s, 1H), 5.54 (d, J=8.8 Hz, 1H), 4.96 (d,J=8.5 Hz, 1H), 4.11 (m, 2H), 3.91 (s, 3H), 3.70 (d, J=8.8 Hz, 1H), 3.48(t, J=6.4 Hz, 2H), 3.37 (d, J=9.0 Hz, 1H), 3.25 (s, 3H), 1.99 (quint,J=6.6 Hz, 2H), 1.25 (s, 3H), 0.46 (s, 3H).

Example 5: Synthesis10-chloro-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [5.1] and [5.2]

Step 1: 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene [5a]

To a mixture of 5-bromo-2-chlorophenol (15 g, 72.3 mmol), and1-bromo-3-methoxypropane (9.7 ml, 87 mmol) in DMF (40 ml) at rt wasadded K₂CO₃ (20 g, 145 mmol), and the resultant mixture was stirred at50° C. for 16 hours. The mixture was then filtered, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography, EtOAc/heptane 0 to 30% to give product (18.4 g, 91%yield). ¹H NMR (400 MHz, Acetonitrile-d3): 7.38-7.20 (m, 2H), 7.10 (dd,J=8.4, 2.1 Hz, 1H), 4.13 (t, J=6.3 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 3.31(s, 3H), 2.09-1.98 (m, 2H).

Step 2:5-(4-chloro-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanone [5b]

A mixture of Pd(OAc)₂ (60 mg, 0.268 mmol), sodium tert-butoxide (3.35 g,34.9 mmol), dicyclohexyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphane (230mg), 2,2-dimethylcyclopentanone (4.04 ml, 32.2 mmol) and4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (7.5 g, 26.8 mmol) intoluene (30.0 mL) was heated in a sealed vial at 50° C. under nitrogenatmosphere for 6 hours. The mixture was diluted with EtOAc and filtered.The filtrated solution was concentrated and the remaining oil waspurified by silica gel column chromatography, EtOAc/heptane 5 to 50%, togive product (3 g, 36% yield). LC-MS (m/z): 311.2 [M+H]⁺.

Step 3:5-(4-Chloro-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanamine[5c]

To the mixture of5-(4-chloro-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanone (3 g,9.65 mmol) in MeOH (30 mL) was added acetic acid ammonia salt (14.8 g,192 mmol) and sodium cyanoborohydride (6.06 g, 97 mmol). The mixture wasstirred at 70° C. for 16 hours and then was concentrated under reducedpressure. The remaining material was diluted with EtOAc, washed withwater and brine, dried over Na₂SO₄ and concentrated. The crude materialwas used in the next step with no further purification. LCMS (m/z):312.0 [M+H]⁺.

Step 4: N-(5-(4-chloro-3-(3-methoxypropoxy)phenyl)-2,2dimethylcyclopentyl)formamide [5d]

To the mixture of5-(4-chloro-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanamine (3g, 9.65 mmol) in dioxane (25 ml) was added formic acid (1.48 ml, 38.6mmol). The mixture was stirred at 100° C. for 6 hours. The mixture wasconcentrated to afford the crude product which was used in the next stepwith no further purification. LCMS (m/z): 340.2 [M+H]⁺.

Step 5:7-chloro-8-(3-methoxypropoxy)-3,3-dimethyl-2,3,3a,9b-tetrahydro-1H-cyclopenta[c]isoquinoline[rac-5e-1 and rac-5e-2]

To a mixture ofN-(5-(4-chloro-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentyl)formamide(3.28 g, 9.65 mmol) in acetonitrile (17 ml) was added POCl₃ (1.35 ml,14.5 mmol). The mixture was stirred at 85° C. for 2 hours and thenconcentrated. The residue was dissolved in EtOAc and basified by addingammonium hydroxide solution. The phases were separated and the organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theremaining material was purified by silica gel chromatography,acetone/heptane 5 to 50% to give product rac-5e-1 and rac-5e-2.

Less polar product: rac-5e-1 trans isomer (590 mg, 19% yield). LCMS(m/z): 322.3 [M+H]⁺.

More polar product: rac-5e-2 cis isomer (470 mg, 15% yield). LCMS (m/z):322.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.25 (s,2H), 6.69 (s, 1H), 4.14 (s, 3H), 3.78 (d, J=10.1 Hz, 1H), 3.60 (s, 3H),3.43-3.32 (m, 4H), 3.26 (q, J=9.5, 9.1 Hz, 2H), 2.47-2.19 (m, 3H),2.16-2.02 (m, 4H), 1.66 (d, J=10.1 Hz, 4H), 1.46 (t, J=8.6 Hz, 3H), 1.23(s, 4H), 1.16-1.00 (m, 3H), 0.88 (s, 4H)

The relative configuration of rac-5e-1 and rac-5e-2 was established bynuclear Overhauser effect (NOE) experiments.

Step 6: Ethyl10-chloro-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,8,8a,12b-octahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylate[rac-5f]

To a mixture of7-chloro-8-(3-methoxypropoxy)-3,3-dimethyl-2,3,3a,9b-tetrahydro-1H-cyclopenta[c]isoquinoline(cis isomer, rac-5e-2) (470 mg, 1.46 mmol) in EtOH (5 ml) was added(Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate (816 mg, 4.38 mmol). Themixture was stirred at 110° C. for 16 hours. After cooling, the mixturewas concentrated and the crude material was used in the next step withno further purification. LCMS (m/z): 462.0 [M+H]⁺.

Step 7: Ethyl(3aS,12bR)-10-chloro-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylate[5g-1] and [5g-2]

To a mixture of rac-5f ((673.7 mg, 1.461 mmol) in DME (3.5 ml) was addedp-chloranil (359.6 mg, 1.461 mmol) and the mixture was stirred at 110°C. for 2 hours. After cooling to rt, the mixture was concentrated andthe residue was purified by silica gel column chromatography, MeOH/DCM 0to 6%, to give product (180 mg). LCMS (m/z): 460.0 [M+H]⁺. This productwas separated by chiral SFC (AD column, flow rate 100 ml/min,CO₂/MeOH=75/25) to give two enantiomers: 5g-1 (tR 3.55 min, 70 mg, 11%yield) and 5g-2 (tR 4.91 min, 70 mg, 11% yield).

Step 8:(3aS,12bR)-10-chloro-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [5.1]

To a mixture of 5g-1 (70 mg, 0.152 mmol) in EtOH (1 ml) was added NaOH(5 M, 0.152 ml, 0.761 mmol). After stirring at rt for 2 hours, themixture was concentrated and then acidified by adding 3.0 N HCl aqsolution. To the mixture was added EtOAc. The organic layer was washedwith water and brine, dried, and concentrated. The crude residue waspurified by silica gel column chromatography, MeOH in DCM 0 to 5%, togive product (50 mg, 75% yield). LCMS (m/z): 432.2 [M+H]⁺. ¹H NMR (400MHz, Acetonitrile-d3): 8.40 (s, 1H), 8.01 (s, 1H), 7.22 (s, 1H), 7.09(s, 1H), 4.39 (d, J=8.6 Hz, 1H), 4.24 (ddt, J=15.9, 9.6, 4.8 Hz, 2H),4.08 (q, J=7.1 Hz, 4H), 3.83 (t, J=6.8 Hz, 1H), 3.57 (t, J=6.1 Hz, 2H),3.32 (s, 3H), 2.48-2.24 (m, 3H), 2.15 (s, 2H), 2.07 (p, J=6.2 Hz, 3H),1.66 (ddd, J=13.9, 8.1, 6.0 Hz, 1H), 1.56-1.40 (m, 1H), 1.28-1.16 (m,8H), 0.47 (s, 3H).

Step 9:(3aR,12bS)-10-chloro-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [5.2]

To a mixture of 5g-2 (70 mg, 0.152 mmol) in EtOH (1 ml) was added NaOH(5 M, 0.152 ml, 0.761 mmol). After stirring at rt for 2 hours, themixture was concentrated and then acidified by adding 3.0 N HCl aqsolution. To the mixture was added EtOAc. The organic layer was washedwith water and brine, dried, and concentrated. The crude residue waspurified by silica gel column chromatography, MeOH in DCM 0 to 5%, togive product (59 mg, 79% yield). LCMS (m/z): 432.2 [M+H]⁺. ¹H NMR (400MHz, Acetonitrile-d3): 8.40 (s, 1H), 8.01 (s, 1H), 7.22 (s, 1H), 7.09(s, 1H), 4.39 (d, J=8.6 Hz, 1H), 4.24 (ddt, J=15.9, 9.6, 4.8 Hz, 2H),4.08 (q, J=7.1 Hz, 4H), 3.83 (t, J=6.8 Hz, 1H), 3.57 (t, J=6.1 Hz, 2H),3.32 (s, 3H), 2.48-2.24 (m, 3H), 2.15 (s, 2H), 2.07 (p, J=6.2 Hz, 3H),1.66 (ddd, J=13.9, 8.1, 6.0 Hz, 1H), 1.56-1.40 (m, 1H), 1.28-1.16 (m,8H), 0.47 (s, 3H).

Example 6:10-methoxy-11-(3-methoxypropoxy)-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [6.1 and 6.2]

Step 1. 2-(4-methoxy-3-(3-methoxypropoxy)phenyl)cyclopentan-1-one. [6a]

To a solution of 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (5 g,18.24 mmol) in 1,4-Dioxane (100.0 mL) was added NaOAc (1.49 g 18.24mmol), cyclopentanone (4.59 g, 54.74 mmol), pyrrolidine (0.259 g, 3.64mmol), P(O-Tol)₃ (0.222 g, 0.72 mmol.) and 1,1,3,3-Tetramethylbutylamine(0.471 g, 3.64 mmol) at room temperature under nitrogen atmosphere. Thereaction mixture was purged with nitrogen. To the above reactionmixture, Pd(OAc)₂ (0.0817 g, 0.364 mmol) was added and the mixture wasagain purged with nitrogen and then heated at 110° C. for 15 hs. Aftercooled at rt, the reaction mixture was filtered through celite bed, thebed was further washed with ethyl acetate. The filtrate was washed withwater, brine, and dried over sodium sulfate, filtered, and concentrated.The residue was purified by silica gel column chromatography,(EtOAc/Hexane, 20-30%) to give product. LCMS (m/z): 279.35 [M+H]⁺

Step 2.1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3,3-dimethylbutan-2-amine.[6b]

NH₄OAc (8.73 g, 113 mmol) and NaBH₃CN (0.949 g, 15.1 mmol) were addedtemperature to a solution of 6a (2.1 g, 7.55 mmol) in MeOH (15.1 mL) atrt and the resulting mixture was stirred at room temperature for 18hours. The reaction was then quenched by adding 20% NaOH aqueoussolution and stirred at rt for 20 minutes. The reaction mixture wasextracted with EtOAc. The organic layer was washed with water, brine,dried over sodium sulfate and concentrated to give product 6b (2.1 gcrude). LCMS (m/z):281.2 [M+H]⁺

Step 3.N-(1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3,3-dimethylbutan-2-yl)formamide[6c]

To a solution of 6b (2.0 g, 7.16 mmol) in DMF (11.9 mL) at 0° C. wasadded EDC.HCl (2.73 g, 14.3 mmol), DIPEA (2.77 g, 21.5 mmol), followedby formic acid (1.31 g, 28.6 mmol). After stirred at rt for 1 h, coldwater was added to above reaction mixture and the mixture was extractedwith EtOAc. The organic layer was washed with 10% NaHCO₃ aq. solution,10% HCl aq. solution, water and brine. The separated organic layer wasdried over sodium sulfate, filtered and concentrated to give product. 6c(1.4 g). The crude material was used in the next step with no furtherpurification. LCMS (m/z): 308.1 [M+H]+

Step 4.7-methoxy-8-(3-methoxypropoxy)-2,3,3a,9b-tetrahydro-1H-cyclopenta[c]isoquinoline.[6d-1] and [6d-2]

POCl₃ (0.778 g, 5.07 mmol) was added to a solution of 6c (1.30 g, 4.23mmol) in CH₃CN (21.15 mL) at 0° C. and the reaction mixture was heatedat 80° C.) for 3 hours. The reaction mixture was concentrated undervacuum and the residue was dissolved in ethyl acetate. Ammonia solution(27% in water) was added under stirring until the pH=11. The mixture wasthen extracted with ethyl acetate. The combined ethyl acetate layers waswashed with water, brine, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography gave twoisomers. 6d-1 (0.425 g, less polar product) and 6d-2 (0.3 g, more polarisomer).

6d-1: LCMS (m/z): 290.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.23 (d, J=3.1Hz, 1H), 6.92 (s, 1H), 6.75 (d, J=8.8 Hz, 1H), 4.19 (t, J=6.5 Hz, 2H),3.90 (s, 3H), 3.60 (t, J=6.0 Hz, 3H), 3.39 (d, J=9.1 Hz, 4H), 3.21-3.15(m, 1H), 2.60-2.51 (m, 1H), 2.30-2.11 (m, 5H), 1.98-1.90 (m, 2H), 1.82(dt, J=19.6, 11.4 Hz, 2H).

6d-2: LCMS (m/z): 290.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.16 (s, 1H),6.84 (s, 1H), 6.75 (s, 1H), 4.18 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.60(t, J=6.0 Hz, 2H), 3.38 (s, 3H), 2.91 (dd, J=17.4, 8.6 Hz, 1H), 2.34(dd, J=14.8, 7.0 Hz, 1H), 2.20-2.10 (m, 3H), 2.08-1.95 (m, 3H),1.67-1.55 (m, 3H), 1.60-1.44 (m, 2H), 0.97-0.82 (m, 2H).

Step 5. Ethyl10-methoxy-11-(3-methoxypropoxy)-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylate[6e-1]

A solution of 6d-1 (0.425 g, 1.45 mmol) and ethyl(E)-2-(ethoxymethylene)-3-oxobutanoate (0.810 g, 4.35 mmol) in EtOH (9ml) was heated at 110° C. for 18 hours. The mixture was thenconcentrated under vacuum and the residue was dissolved in DME (20.0mL). p-chloranil (0.426 g, 1.73 mmol) was added and the reaction mixturewas heated to reflux for 2 hours. After volatile solvent was removedunder vacuum, diethyl ether was added. The precipitate was collected byfiltration to afford product. LCMS (m/z): 428.3 [M+H]⁺.

Step 6.10-methoxy-11-(3-methoxypropoxy)-7-oxo-1,2,3,3a,7,12b-hexahydrocyclopenta[c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [6.1] and [6.2]

To a solution of 6e-1 (0.075 g, 0.175 mmol) in MeOH (6.0 mL), LiOH.2H₂O(0.014 g, 0.35 mmol) was added followed by the addition of water (2.0mL) at rt. The reaction mixture was then stirred at rt for 2 hours.After completion of reaction, the reaction mixture was concentratedunder vacuum. The residue was dissolved into cold water and wasacidified to pH 4-5 using dil. HCl. The obtained solid was filtered,washed with cold water and diethyl ether. The solid was dried well undervacuum to give off white solid as the desired product 6.1 (0.029 g, 41%yield). LCMS (m/z): [M+H]⁺ 400.0. ¹H NMR (400 MHz, DMSO): 16.83 (s, 1H),8.80 (s, 1H), 7.54 (d, J=3.3 Hz, 2H), 7.07 (s, 1H), 5.01-4.74 (m, 1H),4.29-4.00 (m, 2H), 3.89 (s, 3H), 3.57 (s, 1H), 3.48 (t, J=6.2 Hz, 2H),3.34 (s, 3H), 2.37 (s, 1H), 2.23 (d, J=8.5 Hz, 1H), 2.08 (d, J=6.6 Hz,1H), 2.01-1.90 (m, 2H), 1.64 (s, 1H), 1.49 (s, 2H).

Compound 6.2 was synthesized from compound 6d-2 following the proceduresStep 5-6 described for the synthesis of 6.1. LCMS (m/z): [M+H]⁺ 400.0.¹H NMR (400 MHz, DMSO): 16.77 (s, 1H), 8.38 (s, 1H), 7.52 (d, J=20.7 Hz,2H), 6.85 (s, 1H), 4.13 (t, J=6.4 Hz, 2H), 3.89 (s, 3H), 3.48 (t, J=6.2Hz, 2H), 3.26 (s, 3H), 3.09 (dd, J=19.7, 12.1 Hz, 1H), 2.38 (s, 1H),2.10-1.92 (m, 5H), 1.70 (s, 1H).

Note: isomers 6.1 and 6.2 were isolated and tested separately, but thestereochemistry of the isomers was not apparent from their nmr data.

Example 7: (3aR,12bR)-8-fluoro-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-2H-furo[3,2-c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [7.1]

Step 1:4-hydroxy-1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3,3-dimethylbutan-2-one[7.1a]

A mixture of 4.1a (8.8 g, 21.97 mmol) and 10% Pd/C (2.1 g, 1.973 mmol)in MeOH (110 ml) was purged with vacuum and H₂ was stirred for 2 days.The atmosphere was purged with vacuum, and the mixture was filteredthrough diatomaceous earth with MeOH washes, and concentrated to providea grey oil that was taken up in EtOAc and passed through a small pad ofSiO₂, and the concentrated to provide 7.1a (6.66 g, 21.46 mmol, 98%yield) as a yellow oil. LC-MS (m/z): 311.3 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 6.82 (d, J=8.24 Hz, 1H), 6.73 (s, 1H), 6.70 (d, J=8.10 Hz, 1H),4.10 (t, J=6.41 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 2H), 3.55-3.60 (m, 4H),3.35 (s, 3H), 2.36 (br, 1H), 2.10 (quin, J=6.33 Hz, 2H), 1.23 (s, 6H).

Step 2:2-(4-methoxy-3-(3-methoxypropoxy)phenyl)-4,4-dimethyldihydrofuran-3(2H)-one[7.1b]

A 2-neck, oven dried 250 mL round-bottomed flask was fitted apressure-equalizing addition funnel and with charged with 7.1a (6.63 g,21.36 mmol) and 50 mL DCM. The flask was cooled to 0° C. The additionfunnel was charged with Br₂ (1.045 ml, 20.29 mmol) in 485 mL DCM, whichwas added dropwise over 25 min. Immediately after complete addition, themixture was poured in to 200 mL sat aq. Na₂S2O₃ and stirred for 20 min.The mixture was extracted thrice with EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrate onto 13 g diatomaceousearth. The crude material was purified on a 80 g RediSep SiO₂ cartridge(0-60% EtOAc in heptanes) to provide 7.1 b (3.89 g, 12.61 mmol, 59.1%yield) as a yellow oil from the first major UV-active peak. LC-MS (m/z):309.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 6.97 (s, 1H), 6.96 (d, J=7.96 Hz,1H), 6.87 (br d, J=8.12 Hz, 1H), 4.76 (s, 1H), 4.08-4.17 (m, 3H), 3.96(d, J=9.2 Hz, 1H), 3.85 (s, 3H), 3.57 (t, J=6.13 Hz, 2H), 3.35 (s, 3H),2.10 (quint, J=6.3 Hz, 2H), 1.20 (s, 3H), 1.16 (s, 3H).

Step 3:N-(2-(4-methoxy-3-(3-methoxypropoxy)phenyl)-4,4-dimethyltetrahydrofuran-3-yl)formamide[7.1c]

A 250 mL round-bottomed flask was charged with 7.1b (3.7 g, 12.00 mmol)and MeOH (30.0 ml). NH₄OAc (18.50 g, 240 mmol), was added, followed byNaBH₃CN (2.262 g, 36.0 mmol). The flask was fitted with a condenser andrefluxed overnight. At 20 h, the mixture was cooled to rt and 30 mL 20wt % NaOH (aq) was added. After stirring for 1 h, diluted slightly withwater, extracted thrice with 2-MeTHF. The combined organic layers weredried over Na₂SO₄, filtered and concentrated to provide a heterogenousmixture. The mixture was taken up in DCM (30.0 ml). NEt₃ (10.03 ml, 71.9mmol) was added, followed by formic acid (1.840 ml, 48.0 mmol) and EDC(9.19 g, 48.0 mmol). At 1 h complete, the mixture was poured into 20 mLwater, 60 mL EtOAc and the layer separated. The organic layer was washedtwice with N NaHSO₄, once with brine, dried over Na₂SO₄, filtered andconcentrated onto diatomaceous earth. The crude material was purified ona 40 g RediSep SiO₂ cartridge (0->70% acetone in heptane) to provide7.1c (2.58 g, 7.65 mmol, 63.8% yield) as a yellow oil. LC-MS (m/z):338.3 [M+H]⁺.

Step 4:rac-(3aR,9bR)-7-methoxy-8-(3-methoxypropoxy)-3,3-dimethyl-2,3,3a,9b-tetrahydrofuro[3,2-c]isoquinoline[7.1d]

A 200 mL round-bottomed flask was charged with 7.1c (2.6 g, 7.71 mmol)and purged with N₂. MeCN (30.8 ml), followed by POCl₃ (1.077 ml, 11.56mmol). The flask was fitted with a condenser and then heated to 70° C.At 30 min, the mixture was cooled to rt and the volatiles were removedunder reduced pressure. The oil was diluted with EtOAc and water, andbasisified with sat. aq. NH₄OH to pH 11. The layers were separated, andthe aqueous layer extracted twice with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrate onto 6 gdiatomaceous earth. The crude material was purified on a 40 g RediSepSiO₂ cartridge (0->70% acetone in heptane). The most polar UV-activepeak was isolated as 7.1d (900 mg, 2.82 mmol, 36.6% yield), which wasshown to be the cis isomer by 2D NMR. LC-MS (m/z): 320.3 [M+H]. ¹H NMR(500 MHz, CDCl₃) δ 8.27 (s, 1H), 6.98 (s, 1H), 6.86 (s, 1H), 4.97 (d,J=7.33 Hz, 1H), 4.14-4.23 (m, 2H), 3.87-3.94 (m, 4H), 3.48-3.60 (m, 3H),3.39 (d, J=7.80 Hz, 1H), 3.35 (s, 3H), 2.12 (quin, J=6.33 Hz, 2H), 1.37(s, 3H), 1.14 (s, 3H).

Step 5: rac-ethyl(3aR,12bR)-8-fluoro-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-2H-furo[3,2-c]pyrido[2,1-a]isoquinoline-6-carboxylate[7.1e]

To a suspension of ZnI₂ (200 mg, 0.626 mmol) and 7.1d (200 mg, 0.626mmol) in dry MeCN (2 mL), was added a solution of 3.1a (553 mg, 1.879mmol) in dry DMF (3 mL), dropwise, at 50° C., and the reaction mixturewas stirred overnight. The reaction mixture was poured into 10% HCl andextracted with DCM. The organic layer was washed with brine, and driedover MgSO₄. After filtration, the organic layer was concentrated ontodiatomaceous earth and purified on a 4 g RediSep SiO₂ cartridge (0->60IPA in EtOAc) to provide 7.1e (90 mg, 0.184 mmol, 30.6% yield) as abrown solid. LC-MS (m/z): 476.3 [M+H]⁺.

Step 6:(3aR,12bR)-8-fluoro-10-methoxy-1-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-2H-furo[3,2-c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [7.1]

7.1g (90 mg, 0.189 mmol) was suspended in THF (1.5 ml). Aq. LiOH (500μl, 1.000 mmol) was added and the mixture was stirred overnight. The pHwas adjusted to 1 with 4 N HCl. The mixture was extracted thrice withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to provide a light brown solid. The material was purifiedby chiral SFC (AD column, flow rate 100 ml/min, CO₂/MeOH=80/20, 250 bar)to give two enantiomers 7.1 (tR 4.56, 17.7 mg, 21%) and 7.2 (tR 2.89min, 17.3 mg, 21%). Compound 7.1: LC-MS (m/z): 448.3 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 8.36 (s, 1H), 7.72 (s, 1H), 7.21 (s, 1H), 5.54 (d, J=7.6Hz, 1H) 4.42 (d, J=6.4 Hz, 1H), 4.16-4.31 (m, 2H) 3.92 (s, 3H), 3.78 (d,J=8.5 Hz, 1H), 3.52-3.69 (m, 2H), 3.42 (br d, J=9.22 Hz, 1H), 3.37 (s,3H), 2.10-2.22 (m, 2H), 1.40 (s, 3H) 0.58 (s, 3H)

Example 8:(3aS,12bR)-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-1H-furo[3,4-c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [8.1]

Step 1:3-hydroxy-1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-2-one[8.1a]

A 200 mL round-bottomed flask was charged with4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (13.0 g, 47.2 mmol),NaOt-Bu (13.62 g, 142 mmol), xantphos (0.820 g, 1.417 mmol), Pd₂dba₃(0.649 g, 0.709 mmol) and THF (Volume: 140 mL). To the mixture was added3-hydroxy-3-methylbutan-2-one (9.65 g, 94 mmol). The flask was fittedwith a reflux condenser and the mixture was heated to 65° C. in analuminum chip bath for 3.5 h. After cooling, the mixture was filteredthrough diatomaceous earth with EtOAc and water washes. The pH of theaqueous layer was adjusted to 2, the layers were separated, and theaqueous layer extracted twice with EtOAc. The combined organic layerswere dried over Na₂SO₄, filter, and concentrated onto 6 g diatomaceousearth. The material was purified by silica gel column chromatography,EtOAc/heptane 0 to 70% to give product (5.7 g, 19.23 mmol, 40.7% yield).LC-MS (m/z): 297.3 [M+H]⁺.

Step 2:4-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylfuran-3(2H)-one[8.1 b]

8.1a (1.43 g, 4.83 mmol) was dissolved in toluene (19.30 ml).Bredereck's reagent (1.993 ml, 8.69 mmol) was added, and the flaskfitted with reflux condenser and heated to 100° C. for 1 h. Aftercooling to rt, 3 g of diatomaceous earth was added and the volatileswere removed. The material was purified by silica gel columnchromatography, EtOAc/heptane 0 to 50% to provide product 8.1 b (1.26 g,85% yield) as a yellow oil. LC-MS (m/z): 307.2 [M+H]⁺. ¹H NMR (500 MHz,CHLOROFORM-d): 8.39 (s, 1H), 7.31 (d, J=1.89 Hz, 1H), 7.22 (dd, J=8.35,2.05 Hz, 1H), 6.88 (d, J=8.20 Hz, 1H), 4.16 (s, 2H), 3.87 (s, 3H), 3.58(s, 2H), 3.36 (s, 3H), 2.13 (quin, J=6.38 Hz, 2H), 1.46 (s, 6H).

Step 3:4-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethyldihydrofuran-3(2H)-one[8.1c]

8.1b (1.26 g, 4.11 mmol) was taken up in EtOH (10.28 ml) and THF (10.28ml). The mixture was cooled to 0° C. and NaBH₄ (0.202 g, 5.35 mmol) wasadded. After 2 h, the reaction was quenched with saturated aq. NH₄Cl andextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated to provide an oil. The oil was chargedto a 100 mL round-bottomed flask and dissolved in DCM (32 mL). Themixture was cooled to 0° C. and DMP (4104 mg, 9.68 mmol) was added as asingle portion. After 2 h, the reaction mixture was filter throughdiatomaceous earth with DCM and sat. aq. NaHCO₃. The layers wereseparated. The aqueous layer was extract twice with DCM. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated toprovide a yellow oil which was purified by silica gel columnchromatography, EtOAc/heptane 0 to 70% to give product 8.1c (841 mg,42.3% yield). LC-MS (m/z): 309.2 [M+H]⁺.

Step 4:N-(4-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethyltetrahydrofuran-3-yl)formamide[8.1 d]

A 20 mL vial was charged with 8.1c (840 mg, 2.72 mmol) and methanol (8ml). Ammonium acetate (3.15 g, 40.9 mmol) was added and the mixturestirred until homogeneous. Sodium cyanoborohydride (0.342 g, 5.45 mmol)was added as a single portion. The yellow solution was stirred overnightat 60° C. At 20 h, The mixture was cool to rt and quenched with 6 mL 5 MNaOH (20 wt %). After 1 h, the mixture was extracted with EtOAc twice,dried over Na₂SO₄, filtered and concentrated to provide a yellow oil.The oil was taken up in formic acid (5.0 ml, 130 mmol) and dioxane (7ml) in an 8 mL vial. The vial was sealed and heated to 98° C. 18 h. Thevolatiles were removed under reduced pressure ° (50 C, 18 mbar) and theresultant oil azeotroped twice with 30 mL toluene before a finalconcentration onto diatomaceous earth with MeOH and DCM. The crudematerial was purified by silica gel column chromatography,acetone/heptane 0->50% to give product 8.1d (230 mg, 25.1% yield) as awhite solid. LC-MS (m/z): 338.1 [M+H]⁺.

Step 5:7-methoxy-8-(3-methoxypropoxy)-3,3-dimethyl-1,3,3a,9b-tetrahydrofuro[3,4-c]isoquinoline[8.1e]

A 50 mL round-bottomed flask was charged with 8.1d (230 mg, 0.682 mmol)and purged with vacuum and back-filled with nitrogen. MeCN (3.41 ml) wasadded, followed by POCl₃ (0.095 ml, 1.022 mmol). The flask was fittedwith a condenser and heated to 70° C. At 2 h, cooled to rt and thevolatiles were removed under vacuum. The remaining oil was diluted with40 mL EtOAc, and 10 mL water, and then basified with ammonium hydroxidesolution until pH 11. The layers were separated, and the aqueous layerextracted EtOAc. The combined organic layers were dried over Na₂SO₄,filtered and concentrated onto diatomaceous earth. The crude materialwas purified by silica gel column chromatography, acetone/heptane 0 to50%, to give product 8.1e (202 mg, 93% yield). LC-MS (m/z): 320.2[M+H]⁺.

Step 6: ethyl(3aS,12bR)-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-1H-furo[3,4-c]pyrido[2,1-a]isoquinoline-6-carboxylate[8.1f]

A 4 mL vial was charged with 8.1e (200 mg, 0.626 mmol) in EtOH (1.5 ml).Added ethyl (E)-2-(ethoxymethylene)-3-oxobutanoate (408 mg, 2.192 mmol).The vial was sealed, purged with N2, and heated to 85° C. overnight. Anadditional 400 mg ethyl (E)-2-(ethoxymethylene)-3-oxobutanoate wasadded. After 5 h, the volatiles were removed under vacuum. The oil wastaken up in DME (1.3 mL) and p-chloroanil (185 mg) was added. Themixture was heated at 100° C. for 30 min. After cooling at rt, thesolvent was removed on rotovap and 5 mL ether was added and the solidfiltered. The black solid was taken up in MeOH and loaded ontodiatomaceous earth, and then purified by silica gel columnchromatography, IPA/EtOAc 0 to 70 to give product. The stereoisomerswere separated by chiral HPLC (AD column, flow rate 1 mL/min,heptane/IPA=60/40). Peak 3 (tR 6.76 min) was isolated as 8.1f (13.5 mg,0.030 mmol, 4.71% yield). LC-MS (m/z): 458.4 [M+H]⁺.

Step 7:(3aS,12bR)-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-3,3a,7,12b-tetrahydro-1H-furo[3,4-c]pyrido[2,1-a]isoquinoline-6-carboxylicacid [8.1]

To a solution of 8.1f (12.5 mg, 0.027 mmol) in THF (1 mL) was added NaOH(0.022 mL, 0.109 mmol) and stirred overnight. The solution was acidifiedby adding 4.0 N HCl aq solution and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄ and concentrated to provide ayellow oil, which was purified by HPLC (Kinetex column, 0.1% TFA inH₂O/MeCN, 1.2 mL/min) to provide 8.1 (7.8 mg, 52%). ¹H NMR (500 MHz,DMSO-d₆): 8.62 (s, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.11 (s, 1H), 5.04(br d, J=8.75 Hz, 1H), 4.40 (br dd, J=9.81, 1.30 Hz, 1H), 4.17-4.26 (m,3H), 4.11 (dt, J=9.75, 6.47 Hz, 2H), 3.94-4.00 (m, 1H), 3.91 (s, 3H),3.50 (br t, J=6.27 Hz, 2H), 3.27 (s, 3H), 2.00 (dt, J=12.65, 6.21 Hz,2H), 1.39 (s, 3H), 0.64 (s, 3H). LC-MS (m/z): 430.1 [M+H]⁺.

Example 9: Synthesis11-methoxy-12-(3-methoxypropoxy)-4,4-dimethyl-8-oxo-2,3,4,4a,8,13b-hexahydro-1H-pyrido[1,2-f]phenanthridine-7-carboxylicacid [9.1] and [9.2]

Step 1: 6-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclohexanone [9.1a]

A mixture of Pd(OAc)₂ (14 mg, 0.064 mmol), sodium tert-butoxide (0.795g, 8.27 mmol), dicyclohexyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphane (58mg), 2,2-dimethylcyclohexanone (1.056 ml, 7.63 mmol) and4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (1.75 g, 6.36 mmol) intoluene (6.0 ml) was heated in a sealed vial under nitrogen atmosphereat 50° C. for 18 hours. The mixture was diluted with EtOAc and washedwith sat sodium bicarbonate. The organic layer was separated, dried overNa₂SO₄, filtrated and concentrated. The remaining oil was purified bysilica gel column chromatography, EtOAc/heptane 5 to 50%, to giveproduct (1 g, 49.1% yield). LC-MS (m/z): 321.2 [M+H]⁺.

Step 2:6-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclohexan-1-amine[9.1 b]

To the mixture of5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclohexanone (500mg, 1.56 mmol) in MeOH (5 ml) was added acetic acid ammonia salt (2.4 g,31.2 mmol) and sodium cyanoborohydride (981 mg, 15.4 mmol). The mixturewas stirred at 70° C. for 8 hours and then was concentrated underreduced pressure. The remaining material was diluted with EtOAc, washedwith water and brine, dried over Na₂SO₄ and concentrated. The crudematerial was used in the next step without further purification. LCMS(m/z): 322.0 [M+H]⁺.

Step 3: N-(5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2dimethylcyclohexyl)formamide [9.1c]

To the mixture of5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclohexamine (500mg, 1.56 mmol) in dioxane (5 ml) was added formic acid (0.286 mL, 6.22mmol). The mixture was stirred at 100° C. for 6 hours. The mixture wasconcentrated to afford the crude product which was used in the next stepwithout further purification. LCMS (m/z): 350.2 [M+H]⁺.

Step 4:8-methoxy-9-(3-methoxypropoxy)-4,4-dimethyl-1,2,3,4,4a,10b-hexahydrophenanthridine[9.1d]

To a mixture ofN-(5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclohexyl)formamide(543 mg, 1.54 mmol) in acetonitrile (3 ml) was added POCOl₃ (217 μl,2.33 mmol). The mixture was stirred at 85° C. for 2 hours and thenconcentrated. The residue was dissolved in EtOAc and basified byammonium hydroxide solution. The phases were separated and the organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theremaining material was purified by silica gel chromatography,acetone/heptane 5 to 50% to give the title product. (320 mg, 62% yield).LCMS (m/z): 332.3 [M+H]⁺.

Step 5: Ethyl(11-methoxy-12-(3-methoxypropoxy)-4,4-dimethyl-8-oxo-2,3,4,4a,8,9,9a,13b-octahydro-1H-pyrido[1,2-f]phenanthridine-7-carboxylate[9.1e]

To a mixture of8-methoxy-9-(3-methoxypropoxy)-4,4-dimethyl-1,2,3,4,4a,10b-hexahydrophenanthridine(140 mg, 0.422 mmol) in EtOH (1.6 ml) was added (Z)-ethyl2-(ethoxymethylene)-3-oxobutanoate (236 mg, 1.267 mmol). The mixture wasstirred at 110° C. for 16 hours. After cooling, the mixture wasconcentrated and the crude material was used in the next step withoutfurther purification. LCMS (m/z): 472.0 [M+H]⁺.

Step 6: Ethyl11-methoxy-12-(3-methoxypropoxy)-4,4-dimethyl-8-oxo-2,3,4,4a,8,13b-hexahydro-1H-pyrido[1,2-f]phenanthridine-7-carboxylate[9.1f]

To a mixture of 9.1e (199.7 mg, 0.422 mmol) in DME (1.0 ml) was addedp-chloranil (114.6 mg, 0.464 mmol). The mixture was stirred at 110° C.for 2 hours. After cooling to rt, the mixture was filtered and the solidwas washed with cold DME. After drying, the desired product (100 mg,50.5% yield over two steps) was obtained as a light yellow solid. LCMS(m/z): 470.0 [M+H]⁺.

Step 7:11-methoxy-12-(3-methoxypropoxy)-4,4-dimethyl-8-oxo-2,3,4,4a,8,13b-hexahydro-1H-pyrido[1,2-f]phenanthridine-7-carboxylicacid [9.1] and [9.2]

To a mixture of 9.1f (50 mg, 0.106 mmol) in THF (0.6 ml), MeOH (0.6 ml)and water (0.6 ml) was added LiOH (7.7 mg, 0.319 mmol). After stirringat rt for 2 hours, the mixture was concentrated and then acidified byadding 3.0 N HCl aq solution. To the resultant mixture was added EtOAc.The organic layer was washed with water and brine, dried, andconcentrated. The crude residue was purified by reverse phase HPLC togive product (10 mg, 21% yield). LCMS (m/z): 442.2 [M+H]⁺. H NMR (400MHz, Acetonitrile-d3): 9.15 (s, 1H), 7.11 (s, 1H), 6.98 (s, 1H), 4.15(dt, J=9.3, 4.7 Hz, 2H), 3.91 (s, 3H), 3.71 (d, J=12.4 Hz, 1H), 3.53 (t,J=6.2 Hz, 2H), 3.32 (s, 3H), 2.98 (td, J=12.2, 5.2 Hz, 1H), 2.74-2.54(m, 1H), 2.12-2.00 (m, 2H), 1.96 (dt, J=4.5, 2.4 Hz, 5H), 1.46 (d,J=29.8 Hz, 9H).

The relative configuration of the product was established to be as shownbelow by nuclear Overhauser effect (NOE) experiments, but the absolutestereochemistry of each enantiomer has not been confirmed.

The racemic material was separated by chiral SFC (OD column, flow rate100 ml/min, CO₂/MeOH=70/30) to give two enantiomers: 9.1 (tR 3.93 min)and 9.2 (tR 6.14 min). The following compounds can be made by similarmethods using starting materials that are known in the art:

BIOLOGICAL EXAMPLES HBV Cell Line

HepG2-Clone42, a Tet-inducible HBV-expressing cell line with a stablyintegrated 1.3mer copy of the HBV ayw strain, was generated based on theTet-inducible HepAD38 cell line with slight modifications. Ladner S K,et al., Antimicrobial Agents and Chemotherapy. 41(8):1715-1720 (1997).HepG2-Clone42 cells were cultured in DMEM/F-12+Glutamax™ (LifeTechnologies, Carlsbad, Calif., USA), supplemented with 10% fetal bovineserum (Life Technologies), G-418 (Corning, Manassas, Va., USA) at afinal concentration of 0.5 mg/mL, and 5 μg/mL Doxycycline (Sigma, St.Louis, Mo., USA) and maintained in 5% CO₂ at 37° C.

HBsAq Assay

HepG2-Clone42 cells were seeded in into black clear-bottom 96-wellplates at a concentration of 6.0×10⁴ cells/well. 24 hours post-seeding,the cells were treated with 200 μl/well of media containing five-foldserial dilutions of compounds in DMSO. DMSO alone was used as the nodrug control. The final DMSO concentration in all wells was 0.5%.

The HBsAg ELISA kit (Alpha Diagnostic International, San Antonio, Tex.,USE, Catalog #4110) was used to determine the level (semi-quantitative)of secreted HBV sAg. The HBSAg ELISA assay was performed following themanufacturer's protocol as described.

Step 1. Pipet 100 μL each of compound or DMSO treated samples into HBsAgELISA plates. Seal plates and incubate at room temp for 60 minutes.Step 2. Aspirate samples and wash three times with Wash Buffer. Dispense100μ of antibody-HRP conjugate to each well. Incubate at room temp for30 minutes.Step 3. Aspirate samples and wash three times with Wash Buffer. Add 100μL of TMB Substrate to all wells and incubate 15 minutes at room temp.Step 4. Dispense 100 μL of Stop Solution to each well. Measureabsorbance of ELISA plate at 450 nm.

Dose Response Curves

Dose-response curves were generated and the EC₅₀ value was defined asthe compound concentration at which HBsAg secretion was reduced 50%compared to the DMSO control.

EC₅₀ values were determined as follows:

-   -   1. Determine the percent of HBsAg secretion inhibition.        Calculate the percent inhibition on of HBsAg secretion        inhibition using the following equation:

100×(X _(C) −M _(B))/(M _(D) −M _(B))

-   -   -   where X_(C) is the absorbance signal from compound-treated            well; M_(B) is average absorbance signal (background signal)            for column 12 (no cells +HBsAg ELISA sample buffer) and            M_(D) is average absorbance signal from DMSO-treated wells.            Then calculate EC₅₀ values by non-linear regression using a            four parameter curve logistic equation.

The curve fit model employed is XLFit Dose Response One Site Model 204:y=(A+((B−A)/(1+(10{circumflex over ( )}((C−x)*D))))) where A is theminimum y value, B is the maximum y value, C is the log EC50 value, andD is the slope factor.

High Throughput Solubility Measurement

-   -   1. Transfer 20 ul of 10 mM DMSO stock solution into a 96 deep        well plate labeled as sample plate and 5 ul to another plate        labeled as compound standard plate.    -   2. Place the buffer plate in a Multi-Tainer MT-4 container (FTS        Systems). Freeze dry overnight to remove DMSO.    -   3. Add 100 ul of Cl-free PBS (pH 6.8) to the dried compound in        the buffer plate and 95 ul of DMSO to the standard plate.    -   4. The buffer plate is be sonicated in a water bath for 10 min.    -   5. The two plates are then placed onto the VWR orbital shaker to        equilibrate for 24 hours at room temperature.    -   6. The buffer plate is centrifuged at 4000 rpm for 30 min.    -   7. Transfer 10 ul aliquots of supernatant from the buffer plate        to a sample plate and dilute 5 fold.    -   8. Inject both compound standard and sample into the        UPLC/UV/CLND/MS to generate multi detector qualitative and        quantitive analytical data.    -   9. Data was processed with Xcalibur. CLND equimolar response was        used for measuring compound concentration of DMSO solution.        UV270 nm or MS relative ratio was used for solubility        determination.

TABLE 1 HBsAg inhibition Compound Structure HBsAg EC₅₀ (nM) 1.1

0.1 1.2

13 rac-2

460 3.1

0.3 3.2

740 4.1

0.3 5.1

6 5.2

0.1 6.1

9 6.2

5 7.1

0.8 7.2

90 8.1

1 9.1

9 9.2

303

TABLE 2 Pharmacokinetic data for selected compounds. Compound 1.1Mice^(a) Rat^(b) Dog^(c) CL (mL/min · kg) 24.6 15.3 6.4 Vss (L/kg) 3.61.3 1.7 T_(1/2term) (h)* 1.6 2.4 5.9 AUC (uM · h) iv 1.5 2.5 3.1 AUC (uM· h) PO 1.7 4.5 5.7 C_(max) (uM) PO 0.57 1.72 1.9 T_(max) p.o. (h) 0.51.33 0.22 Oral BA (% F) 59 97 93 ^(a)iv 1.0 mg/kg, PO 2.0 mg/kg.Formulation: solution in D5W with PEG (20%) and solutol (5%) ^(b)iv 1.0mg/kg, PO 2.0 mg/kg. Formulation: solution in D5W with PEG (20%) andsolutol (5%) ^(c)iv 0.5 mg/kg, PO 1.0 mg/kg. Formulation: solution inD5W with PEG (20%) and solutol (5%)

Compound 3.1

Mice^(a) Rat^(b) Dog^(c) CL (mL/min · kg) 6.9 2.1 1.3 Vss (L/kg) 1.0 0.60.6 T_(1/2term) (h)* 3.8 9.2 7.2 AUC (uM · h) iv 5.5 16.6 13.3 AUC (uM ·h) po 9.5 19.6 26.7 C_(max) (uM) PO 3.0 6.5 6.2 T_(max) p.o. (h) 0.5 0.51.5 Oral BA (% F) 87 57 96 ^(a)iv 1.0 mg/kg, PO 2.0 mg/kg. Formulation:solution in D5W with PEG (20%) and solutol (5%) ^(b)iv 1.0 mg/kg, PO 2.0mg/kg. Formulation: solution in D5W with PEG (20%) and solutol (5%)^(c)iv 0.5 mg/kg, PO 1.0 mg/kg. Formulation: solution in D5W with PEG(20%) and solutol (10%)

Compound 4.1

Mice^(a) Rat^(b) Dog^(c) CL (mL/min · kg) 12.7 4.9 2.7 Vss (L/kg) 1.50.75 1.7 T_(1/2term) (h)* 1.8 1.2 12.3 AUC (uM · h) iv 2.9 8.0 6.2 AUC(uM · h) PO 7.2 10.2 12.8 C_(max) (uM) PO 1.9 2.6 3.3 T_(max) p.o. (h)1.0 2.0 0.8 Oral BA (% F) 100 65 94 ^(a)iv 1.0 mg/kg, PO 2.0 mg/kg.Formulation: solution in D5W with PEG (20%) and solutol (5%) ^(b)iv 1.0mg/kg, PO 2.0 mg/kg. Formulation: 75% PEG300 and 25% D5W ^(c)iv 0.5mg/kg, PO 1.0 mg/kg. Formulation: solution in D5W with 20% PEG and 10%solutol

Comparative Data

The following table provides data for solubility of compounds of theinvention in PBS (phosphate-buffered saline), using a standardsolubility screening method. It also provides data for inhibition of akey cardiac sodium ion channel for selected compounds: inhibition ofNav1.5 is often associated with cardiotoxicity, thus compounds thatexhibit little or no inhibition of this sodium channel are less likelyto cause adverse effects than compounds that inhibit Nav1.5, and arepredicted to be more suitable for development as drugs. Thus thecompound of Example 4.1 is predicted to be safer in this respect thanthe reference compound.

Each of the compounds of the invention exhibited solubility greater than1 mM in PBS buffer. Compounds with higher solubility possess lower risksin achieving the toxicological end points (in animals) and the oraldevelopment pathway (for human) in terms of the bioavailabilitycriteria. A compound of similar structure (Ref. Ex. #132 fromWO2015/113990) lacking the fused ring of the claimed compounds, wasabout 20-fold less soluble; thus the fused ring provides compounds withimproved physical properties for formulation and/or development.

Example No. Solubility (mM) Nav1.5 EC₅₀ (uM) 1.1 2.4 3.1 1.6 4.1 1.6>500

0.086 46 (Ref. Example #132)

1. A compound of formula (I):

wherein: R¹ is H, halo, or C₁-C₃ alkyl; R² is H, halo, CN, C₁-C₃ alkyl,C₁-C₃ haloalkyl, or C₁-C₃ alkoxy; R³ is OH, halo, CN, C₁-C₃ alkyl, C₃-C₆cycloalkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, or C₁-C₃ haloalkoxy; R⁴ isselected from R¹¹, —OR¹¹, —SR¹, and —NRR¹¹; R¹¹ is C₁-C₄ alkyl, C₃-C₆cycloalkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each ofwhich is optionally substituted with up to three groups selected fromhalo, CN, —OR, C₁-C₃ haloalkoxy, —NR₂, and a 4-7 membered heterocyclicgroup containing one or two heteroatoms selected from N, O and S as ringmembers that is optionally substituted with one or two groups selectedfrom halo, oxo, CN, R, —OR, and —NR₂; R is independently selected ateach occurrence from H and C₁-C₃ alkyl optionally substituted with oneto three groups selected from halo, —OH, C₁-C₃ alkoxy, oxo, CN, —NH₂,—NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂, and cyclopropyl; and two R groupsdirectly attached to the same atom, which may be C or N, can optionallybe taken together to form a 3-6 membered ring that can optionallycontain an added heteroatom selected from N, O and S as a ring member,and can be substituted by up to two groups selected from —OH, oxo, C₁-C₃alkyl, and C₁-C₃ alkoxy; R⁵ is H, halo, CN, C₁-C₃ alkyl, or C₁-C₃haloalkyl; R⁶ is H, halo, C₁-C₃ alkoxy, or C₁-C₆ alkyl; R⁷ is II, halo,C₁-C₃ alkoxy, or C₁-C₆ alkyl; R⁸ is H or C₁-C₆ alkyl; R⁹ taken togetherwith one group selected from R⁶, R⁷ and R⁸ forms a 3-7 memberedcycloalkyl ring or a 3-7 membered heterocyclic ring containing N, O or Sas a ring member; wherein the cycloalkyl or heterocyclic ring isoptionally substituted with up to three groups selected from R, —OR,—NR₂, halo, CN, COOR, CONR₂, and oxo; W is —COOR¹⁰, —C(O)NH—SO₂R,—C(O)NH—SO₂NR₂, 5-tetrazolyl, or 1,2,4-oxadiazol-3-yl-5(4H)-one; R¹⁰ isH or C₁-C₆ alkyl that is optionally substituted with one or two groupsselected from halo, —OR, oxo, CN, —NR₂, COOR, and CONR₂; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is H.3. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein R² is H or halo.
 4. The compound according toclaim 1 or a pharmaceutically acceptable salt thereof, wherein R³ isC₁-C₃ alkoxy or halo.
 5. The compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein R⁴ is —OR¹¹.
 6. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein R⁵ is H or halo.
 7. The compound according to claim 1or a pharmaceutically acceptable salt thereof, which is of the formula:

wherein R⁹ taken together with R⁷ forms a 3-7 membered cycloalkyl ringor a 3-7 membered heterocyclic ring containing N, O or S as a ringmember; wherein the cycloalkyl or heterocyclic ring is optionallysubstituted with up to three groups selected from R, —OR, —NR₂, halo,CN, COOR, CONR₂, and oxo; or a pharmaceutically acceptable salt thereof.8. The compound according to claim 1, which is of the formula:

wherein R⁹ taken together with R⁸ forms a 3-7 membered cycloalkyl ringor a 3-7 membered heterocyclic ring containing N, O or S as a ringmember; wherein the cycloalkyl or heterocyclic ring is optionallysubstituted with up to three groups selected from R, —OR, —NR₂, halo,CN, COOR, CONR₂, and oxo; or a pharmaceutically acceptable salt thereof.9. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein R¹¹ is C₁-C₄ alkyl, optionally substituted with upto two groups selected from halo, CN, —OR, C₁-C₃ haloalkoxy, and a 4-7membered heterocyclic group containing one or two heteroatoms selectedfrom N, O and S as ring members that is optionally substituted with oneor two groups selected from halo, oxo, CN, R, —OR, and —NR₂.
 10. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein the R¹¹ is selected from —CH₂CH₂OMe, —CH₂CH₂CH₂OMe,—CH₂—OEt, —CH₂CH₂-Q, and —CH₂CH₂CH₂-Q, where Q is selected from


11. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein R⁹ taken together with one group selected from R⁶,R⁷ and R⁸ forms a 4-6 membered cycloalkyl ring or a 5-6 memberedheterocyclic ring containing N, O or S as a ring member; wherein thecycloalkyl or heterocyclic ring is optionally substituted with up tothree groups selected from R, —OR, —NR₂, halo, CN, COOR, CONR₂, and oxo.12. The compound according to claim 1, which is selected from:

and the enantiomers of these compounds; or a pharmaceutically acceptablesalt thereof.
 13. The compound of claim 1, which is selected from:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, wherein R¹ is F.
 15. A pharmaceutical composition, comprising acompound of claim 1 admixed with at least one pharmaceuticallyacceptable carrier.
 16. A method to treat a hepatitis B infection, whichcomprises administering to a patient having a hepatitis B infection acompound of claim 1 or a pharmaceutical composition of claim
 15. 17. Themethod of claim 16, wherein the compound of claim 1 or thepharmaceutical composition of claim 15 is used in combination with anadditional therapeutic agent selected from an interferon orpeginterferon, an HBV polymerase inhibitor, a viral entry inhibitor, aviral maturation inhibitor, a capsid assembly inhibitor, an HBV coremodulator, a reverse transcriptase inhibitor, a TLR-agonist, or animmunomodulator.
 18. A method to inhibit replication of hepatitis Bvirus, which comprises contacting the hepatitis B virus, either in vitroor in vivo, with a compound according to claim 1.